Substituted imidazole compounds as KSP inhibitors

ABSTRACT

The present invention relates to new substituted imidazole compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the derivatives together with pharmaceutically acceptable carriers, and uses of the compounds. The compounds of the invention have the following general formula:

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application Ser. No. 60/706,901, filed Aug. 9, 2005, whichis hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to substituted imidazole compounds andpharmaceutically acceptable salts, esters or prodrugs thereof,compositions of these compounds together with pharmaceuticallyacceptable carriers, and uses of these compounds.

2. State of the Art

Kinesins are motor proteins that use adenosine triphosphate to bind tomicrotubules and generate mechanical force. Kinesins are characterizedby a motor domain having about 350 amino acid residues. The crystalstructures of several kinesin motor domains have been resolved.

Currently, about one hundred kinesin-related proteins (KRP) have beenidentified. Kinesins are involved in a variety of cell biologicalprocesses including transport of organelles and vesicles, andmaintenance of the endoplasmic reticulum. Several KRPs interact with themicrotubules of the mitotic spindle or with the chromosomes directly andappear to play a pivotal role during the mitotic stages of the cellcycle. These mitotic KRPs are of particular interest for the developmentof cancer therapeutics.

Kinesin spindle protein (KSP) (also known as Eg5, HsEg5, KNSL1, orKIF11) is one of several kinesin-like motor proteins that are localizedto the mitotic spindle and known to be required for formation and/orfunction of the bipolar mitotic spindle.

In 1995, the depletion of KSP using an antibody directed against theC-terminus of KSP was shown to arrest HeLa cells in mitosis withmonoastral microtubule arrays (Blangy et al., Cell 83:1159-1169, 1995).Mutations in bimC and cut7 genes, which are considered to be homologuesof KSP, cause failure in centrosome separation in Aspergillus nidulans(Enos, A. P., and N. R. Morris, Cell 60:1019-1027, 1990) andSchizosaccharomyces pombe (Hagan, I., and M. Yanagida, Nature347:563-566, 1990). Treatment of cells with either ATRA (alltrans-retinoic acid), which reduces KSP expression on the protein level,or depletion of KSP using antisense oligonucleotides revealed asignificant growth inhibition in DAN-G pancreatic carcinoma cellsindicating that KSP might be involved in the antiproliferative action ofall trans-retinoic acid (Kaiser, A., et al., J. Biol. Chem. 274,18925-18931, 1999). Interestingly, the Xenopus laevis Aurora-relatedprotein kinase pEg2 was shown to associate and phosphorylate X1Eg5(Giet, R., et al., J. Biol. Chem. 274:15005-15013, 1999). Potentialsubstrates of Aurora-related kinases are of particular interest forcancer drug development. For example, Aurora 1 and 2 kinases areoverexpressed on the protein and RNA level and the genes are amplifiedin colon cancer patients.

The first cell permeable small molecule inhibitor for KSP, “monastrol,”was shown to arrest cells with monopolar spindles without affectingmicrotubule polymerization as do conventional chemotherapeutics such astaxanes and vinca alkaloids (Mayer, T. U., et al., Science 286:971-974,1999). Monastrol was identified as an inhibitor in phenotype-basedscreens and it was suggested that this compound may serve as a lead forthe development of anticancer drugs. The inhibition was determined notto be competitive in respect to adenosine triphosphate and to be rapidlyreversible (DeBonis, S., et al., Biochemistry, 42:338-349, 2003; Kapoor,T. M., et al., J. Cell Biol., 150:975-988, 2000).

In light of the importance of improved chemotherapeutics, there is aneed for KSP inhibitors that are effective in vivo inhibitors of KSP andKSP-related proteins.

SUMMARY OF THE INVENTION

This invention is directed to substituted imidazole compoundsrepresented by the formula I:

wherein:

R¹ is selected from the group consisting of aminoacyl, acylamino,carboxyl, carboxyl ester, alkyl, and substituted alkyl with the provisothat substituted alkyl is not substituted with aryl or substituted aryl;

R² is selected from the group consisting of hydrogen, alkyl, and aryl;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, hydroxy, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic provided that only 1 of R³ orR⁴ is hydroxy;

or R³ and R⁴ together with the nitrogen atom pendent thereto join toform a heterocyclic or substituted heterocyclic;

R⁵ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclic, substitutedheterocyclic, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

or R¹ and R⁵, together with the carbon and nitrogen atoms boundrespectively thereto join to form a heterocyclic or substitutedheterocyclic group;

or when R¹ and R⁵, together with the carbon and nitrogen atoms boundrespectively thereto, do not form a heterocyclic group, then R⁴ and R⁵,together with the atoms bound thereto, form a heterocyclic orsubstituted heterocyclic group;

R⁸ is selected from the group consisting of L-A¹, wherein L is selectedfrom the group consisting of —S(O)_(q)— where q is one or two, and C₁ toC₅ alkylene optionally substituted with hydroxy, halo, or acylamino; and

A¹ is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkyl, and substituted cycloalkyl; and

one of either R⁶ or R⁷ is selected from the group consisting ofcycloalkyl, heterocyclic, aryl and heteroaryl, all of which may beoptionally substituted with —(R⁹)_(m) where R⁹ is as defined herein andm is an integer from 1 to 4, and

the other of R⁶ or R⁷ is selected from the group consisting of hydrogen,halo, and alkyl;

R⁹ is selected from the group consisting of cyano, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —CF₃,alkoxy, substituted alkoxy, halo, and hydroxy;

and when m is an integer from 2 to 4, then each R⁹ may be the same ordifferent;

or pharmaceutically acceptable salts, esters or prodrugs thereof.

DETAILED DESCRIPTION OF THE INVENTION A. Compounds of the Invention

As stated above, compounds of the invention include those of formula I:

wherein:

R¹ is selected from the group consisting of aminoacyl, acylamino,carboxyl, carboxyl ester, alkyl, and substituted alkyl with the provisothat substituted alkyl is not substituted with aryl or substituted aryl;

R² is selected from the group consisting of hydrogen, alkyl, and aryl;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, hydroxy, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic provided that only 1 of R³ orR⁴ is hydroxy;

or R³ and R⁴ together with the nitrogen atom pendent thereto join toform a heterocyclic, or substituted heterocyclic;

R⁵ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclic, substitutedheterocyclic, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl;

or R¹ and R⁵, together with the carbon and nitrogen atoms boundrespectively thereto join to form a heterocyclic or substitutedheterocyclic group;

or when R¹ and R⁵, together with the carbon and nitrogen atoms boundrespectively thereto, do not form a heterocyclic group, then R⁴ and R⁵,together with the atoms bound thereto, form a heterocyclic orsubstituted heterocyclic group;

R⁸ is selected from the group consisting of L-A¹, wherein L is selectedfrom the group consisting of —S(O)_(q)— where q is one or two, and C₁ toC₅ alkylene optionally substituted with hydroxy, halo, or acylamino; and

A¹ is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkyl, and substituted cycloalkyl; and

one of either R⁶ or R⁷ is selected from the group consisting ofcycloalkyl, heterocyclic, aryl and heteroaryl, all of which may beoptionally substituted with —(R⁹)_(m) where R⁹ is as defined herein andm is an integer from 1 to 4, and

the other of R⁶ or R⁷ is selected from the group consisting of hydrogen,halo, and alkyl;

R⁹ is selected from the group consisting of cyano, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —CF₃,alkoxy, substituted alkoxy, halo, and hydroxy;

and when m is an integer from 2 to 4, then each R⁹ may be the same ordifferent;

or pharmaceutically acceptable salts, esters or prodrugs thereof.

In one embodiment of the invention, compounds of the invention arerepresented by formula II:

wherein:

n is 1, 2, or 3;

p is 0, 1, 2, 3, or 4;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, hydroxy, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic, provided that only 1 of R³or R⁴ is hydroxy;

or R³ and R⁴ together with the nitrogen atom pendent thereto join toform a heterocyclic or substituted heterocyclic;

R¹⁰ is selected from the group consisting of hydrogen, alkyl optionallysubstituted with a substituent selected from the group consisting ofhydroxy, alkoxy, substituted alkoxy, amino, substituted amino,acylamino, halo, nitrogen-containing heterocycle, substitutednitrogen-containing heterocycle, nitrogen-containing heteroaryl, andsubstituted nitrogen-containing heteroaryl;

R¹¹ is selected from the group consisting of cyano, alkyl, alkenyl,alkynyl, —CF₃, alkoxy, halo, and hydroxy; and when p is 2, 3, or 4, theneach R¹¹ may be the same or different;

R¹² is alkyl,

R¹³ is hydrogen or alkyl,

R¹⁴ is selected from the group consisting of hydrogen, halo, and alkyl;

or R¹⁰ and R¹², together with the carbon and nitrogen atoms boundrespectively thereto join to form a heterocyclic or substitutedheterocyclic group;

or when R¹⁰ and R¹², together with the carbon and nitrogen atoms boundrespectively thereto, do not form a heterocyclic group, then R⁴ and R¹⁰,together with the atoms bound thereto, form a heterocyclic orsubstituted heterocyclic group;

A² is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkyl, and substituted cycloalkyl;

or pharmaceutically acceptable salts, esters or prodrugs thereof.

In one embodiment, R¹ is alkyl. In another embodiment R¹ is selectedfrom the group consisting of isopropyl, t-butyl, and propyl.

In another embodiment, R² is hydrogen.

In one embodiment R³ and/or R⁴ is selected from the group consisting ofalkyl, substituted alkyl and cycloalkyl, and is selected from the groupconsisting of methyl, methoxyethyl, furan-2-ylmethyl, 2-hydroxyethyl,cyclopropyl and isopropyl.

In one embodiment, R³ and/or R⁴ is aryl or substituted aryl and isselected from the group consisting of 4-cyanophenyl, 3,4-difluorophenyl,2,3,5-trifluorophenyl, 3,5-dinitrophenyl, and phenyl.

In one embodiment, R³ and/or R⁴ is heteroaryl or substituted heteroaryland is selected from the group consisting of thiophen-2-yl,3,5-dimethylisoxazol-4-yl, and 2,6-dichloropyridin-4-yl.

In one embodiment, R³ and/or R⁴ is a heterocyclic group or substitutedheterocyclic group and is tetrahydropyran-4-yl or4-(ethoxycarbonyl)piperidin-4-yl.

In one embodiment, either of R³ or R⁴ or both of R³ and R⁴ are hydrogen.In another embodiment, one of R³ or R⁴ is hydroxy.

In one embodiment, R³ and R⁴ are cyclized with the nitrogen atom boundthereto to form a heterocyclic or substituted heterocyclic, and isselected from the group consisting of 1,1-dioxothiamorpholin-N-yl,1-oxothiamorpholin-1-yl, 2-(aminomethylene)pyrrolidin-N-yl,2-(methoxycarbonyl)pyrrolidin-N-yl, 2,6-dimethylmorpholin-N-yl,3-hydroxypiperidin-N-yl, 3-hydroxypyrrolidin-N-yl,4-(butylsulfonyl)piperazin-N-yl, 4-(cyclopropylsulfonyl)piperazin-N-yl,4-(dimethylamino)piperidin-N-yl, 4-(ethoxycarbonyl)piperazin-N-yl,4-(ethylsulfonyl)piperazin-N-yl, 4-(isopropylsulfonyl)piperazin-N-yl,4-(methylcarbonyl)piperazin-N-yl, 4-(methylsulfonyl)piperidin-N-yl,4-(methysulfonyl)piperazin-N-yl, 4-(morpholin-N-yl)piperidin-N-yl,4-(piperidin-N-yl)piperidin-N-yl, 4-(propylsulfonyl)piperazin-N-yl,4-cyclohexylpiperazin-N-yl, 4-hydroxypiperidin-N-yl,4-isopropylpiperazin-4-yl, 4-methylpiperidin-N-yl, isoxazolidin-2-yl,morpholin-N-yl, piperazin-N-yl, piperidin-N-yl,2-(hydrazinocarbonyl)pyrrolidin-N-yl, and pyrrolidin-N-yl.

In some embodiments, R⁵ is substituted alkyl. In one embodiment, R⁵ (orR¹⁰) is selected from the group consisting of —(CH₂)₃NH₂,—(CH₂)₂CH(CH₂OH)NH₂, —CH₂CH(F)CH₂NH₂, —CH₂-[2-(CH₂OH)pyrrolidin-3-yl],—CH₂-[4-(OH)pyrrolidin-3-yl], —CH₂—C(F)(spiropyrrolidin-3-yl),—(CH₂)₂CH(CH₂F)NH₂, —(CH₂)₂C(CH₃)₂NH₂, —(CH₂)₂CH(CH₃)NH₂,—(CH₂)CH(CH₂OCH₃)NH₂, —(CH₂)₂CH(CH₂F)NHC(O)-[(2-CH₃NHC(O))benzene], and—(CH₂)₂CH(CH₂F)-1,3-dioxo-1,3-dihydroisoindole.

In one embodiment, wherein R¹ and R⁵ and the atoms bound thereto join toform a heterocyclic or a substituted heterocyclic group and theheterocyclic group is 2-oxo-tetrahydropyrimidinyl.

In one embodiment one of R⁶ or R⁷ is aryl or substituted aryl and isselected from the group consisting of phenyl, 3-chlorophenyl,3-fluorophenyl, 2,5-difluorophenyl, and 2,3,5-trifluorophenyl.

In one embodiment, the other of R⁶ or R⁷ (or R¹⁴) is hydrogen.

In one embodiment, L is alkylene and A¹ (or A²) is aryl or substitutedaryl.

In one embodiment, L is methylene and A¹ (or A²) is selected from thegroup consisting of phenyl, 3-fluorophenyl, or 3-hydroxyphenyl.

In one embodiment, R¹ is t-butyl, R² is hydrogen, R³ is hydrogen, L ismethylene, A¹ is phenyl, R⁶ is phenyl or substituted phenyl, R⁷ ishydrogen. In another embodiment R¹ is t-butyl, R² and R³ are hydrogen, Lis methylene, A¹ is phenyl, R⁶ is phenyl substituted with 1 to 2 halosubstituents, such as chloro or fluoro. In one embodiment R¹ is t-butyl,R² and R³ are hydrogen, L is methylene, A¹ is phenyl, R⁵ is substitutedalkyl, such as —(CH₂)₃NH₂, —CH₂CH(F)CH₂NH₂, —(CH₂)₂CH(CH₂F)NH₂,—(CH₂)₂CH(CH₂OCH₃)NH₂, —(CH₂)₂CH(CH₃)NH₂, —(CH₂)₂C(CH₃)₂NH₂ and—(CH₂)₂CH(CH₂OH)NH₂. In some embodiments, R¹ is t-butyl, R² is hydrogen,R³ is hydrogen, L is methylene, A¹ is phenyl, R⁶ is phenyl orsubstituted phenyl, R⁷ is hydrogen, and R⁴ is alkyl. In one embodiment,R¹ is t-butyl and R⁶ is phenyl substituted with fluoro and may be3-fluorophenyl or difluorophenyl. In other embodiments, R¹ is isopropyland R⁶ is phenyl substituted with chloro and may be 3-chlorophenyl.

Representative Compounds of the Invention

Specific compounds within the scope of this invention are exemplified inTables 1, 2, and 3 in the experimental section.

Methods and Compositions of the Invention

Also provided is a composition comprising a compound of formulas I andII (including mixtures and/or salts thereof) and a pharmaceuticallyacceptable excipient or carrier.

In another aspect, the present invention provides methods of treating amammalian patient suffering from a disorder mediated, at least in part,by KSP. Thus, the present invention provides methods of treating amammalian patient in need of such treatment comprising administering tothe patient a therapeutically effective amount of a compound of formulasI and II (including mixtures thereof) either alone or in combinationwith other anticancer agents.

B. Definitions and Overview

As discussed above, the present invention is directed to new substitutedimidazole compounds.

It is to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tolimit the scope of the present invention. It must be noted that as usedherein and in the claims, the singular forms “a,” and “the” includeplural referents unless the context clearly dictates otherwise. In thisspecification and in the claims which follow, reference will be made toa number of terms which shall be defined to have the following meanings:

As used herein, “alkyl” refers to monovalent saturated aliphatichydrocarbyl groups having from 1 to 6 carbon atoms and more preferably 1to 3 carbon atoms. This term is exemplified by groups such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 3, andpreferably 1 to 2, substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,cyano, halogen, hydroxy, nitro, carboxyl, carboxyl ester, cycloalkyl,substituted cycloalkyl, spirocycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —SO₂-alkyl, and—SO₂-substituted alkyl.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupspreferably having from 1 to 5 and more preferably 1 to 3 carbon atomswhich are either straight-chained or branched. This term is exemplifiedby groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—) or (—CH(CH₃)CH₂—) and thelike.

“Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,sec-butoxy, n-pentoxy and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)-cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminoacyl” refers to the group —C(O)NRR where each R is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic and whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxyacyl” or “carboxyl ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl,—C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Alkenyl” refers to alkenyl groups having from 2 to 6 carbon atoms andpreferably 2 to, 4 carbon atoms and having at least 1 and preferablyfrom 1 to 2 sites of alkenyl unsaturation. Such groups are exemplifiedby vinyl, allyl, but-3-en-1-yl, and the like.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl,carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic withthe proviso that any hydroxy substitution is not attached to a vinyl(unsaturated) carbon atom.

“Alkynyl” refers to alkynyl groups having from 2 to 6 carbon atoms andpreferably 2 to 3 carbon atoms and having at least 1 and preferably from1 to 2 sites of alkynyl unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl,carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic withthe proviso that any hydroxy substitution is not attached to anacetylenic carbon atom.

“Amino” refers to the group —NH₂.

“Cyano” refers to the group —CN.

“Substituted amino” refers to the group —NR′R″ where R′ and R″ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl, and where R′ and R″are joined, together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group provided that R′ and R″are both not hydrogen. When R′ is hydrogen and R″ is alkyl, thesubstituted amino group is sometimes referred to herein as alkylamino.When R′ and R″ are alkyl, the substituted amino group is sometimesreferred to herein as dialkylamino. When referring to a monosubstitutedamino, it is meant that either R′ or R″ is hydrogen but not both. Whenreferring to a disubstituted amino, it is meant that neither R′ or R″ ishydrogen.

“Acylamino” refers to the groups —NRC(O)alkyl, —NRC(O) substitutedalkyl, —NRC(O)cycloalkyl, —NRC(O) substituted cycloalkyl,—NRC(O)alkenyl, —NRC(O) substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl, —NRC(O)aryl, —NRC(O) substituted aryl,—NRC(O)heteroaryl, —NRC(O) substituted heteroaryl, —NRC(O)heterocyclic,and —NRC(O) substituted heterocyclic where R is hydrogen or alkyl and

wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Nitro” refers to the group —NO₂.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) in which the condensed ringsmay or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the pointof attachment is at an aromatic carbon atom. Preferred aryls includephenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with from1 to 3 substituents, and preferably 1 to 2 substituents, selected fromthe group consisting of hydroxy, acyl, acylamino, acyloxy, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, amino, substituted amino,aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,carboxyl, carboxyl ester, cyano, thiol, alkylthio, substitutedalkylthio, arylthio, substituted arylthio, heteroarylthio, substitutedheteroarylthio, cycloalkylthio, substituted cycloalkylthio,heterocyclicthio, substituted heterocyclicthio, cycloalkyl, substitutedcycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, aminosulfonyl (NH₂—SO₂—), and substituted amino sulfonyl.

“Aryloxy” refers to the group aryl-O— that includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Carboxyl” refers to —COOH or salts thereof.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including, by way of example,adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and thelike.

“Spirocycloalkyl” refers to cyclic groups from 3 to 10 carbon atomshaving a cycloalkyl ring with a spiro union (the union formed by asingle atom which is the only common member of the rings) as exemplifiedby the following structure:

“Substituted cycloalkyl” refers to a cycloalkyl group, having from 1 to5 substituents selected from the group consisting of alkyl, substitutedalkyl, oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy,nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl and —SO₂-cycloalkyl

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is fluoro or chloro.

“Hydroxy” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl) wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom provided that the pointof attachment is through an atom of the aromatic heteroaryl group. Inone embodiment, the nitrogen and/or the sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls includepyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 3 substituents selected from the same groupof substituents defined for substituted aryl.

“Nitrogen-containing heteroaryl” and “nitrogen-containing substitutedheteroaryl” refers to heteroaryl groups and substituted heteroarylgroups comprising at least one nitrogen ring atom and optionallycomprising other non-nitrogen hetero ring atoms such as sulfur, oxygenand the like.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl whereinheteroaryl and substituted heteroaryl are as defined herein.

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or unsaturated (but not aromatic) group having asingle ring or multiple condensed rings, including fused bridged andspiro ring systems, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygenwithin the ring wherein, in fused ring systems, one or more the ringscan be cycloalkyl, aryl or heteroaryl provided that the point ofattachment is through the heterocyclic ring. In one embodiment, thenitrogen and/or sulfur atom(s) of the heterocyclic group are optionallyoxidized to provide for the N-oxide, sulfinyl, and sulfonyl moieties.

“Substituted heterocyclic” or “substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that aresubstituted with from 1 to 3 of the same substituents as defined forsubstituted cycloalkyl.

Examples of heterocyclyls and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Nitrogen-containing heterocyclic” and “nitrogen-containing substitutedheterocyclic” refers to heterocyclic groups and substituted heterocyclicgroups comprising at least one nitrogen ring atom and optionallycomprising other non-nitrogen hetero ring atoms such as sulfur, oxygenand the like.

“Thiol” refers to the group —SH.

“Alkylthio” or “thioalkoxy” refers to the group —S-alkyl.

“Substituted alkylthio” or “substituted thioalkoxy” refers to the group—S-substituted alkyl.

“Arylthio” refers to the group —S-aryl, where aryl is defined above.

“Substituted arylthio” refers to the group —S-substituted aryl, wheresubstituted aryl is defined above.

“Heteroarylthio” refers to the group —S-heteroaryl, where heteroaryl isdefined above.

“Substituted heteroarylthio” refers to the group —S-substitutedheteroaryl, where substituted heteroaryl is defined above.

“Heterocyclicthio” refers to the group —S-heterocyclic and “substitutedheterocyclicthio” refers to the group —S-substituted heterocyclic, whereheterocyclic and substituted heterocyclic are defined above.

“Heterocyclyloxy” refers to the group heterocyclyl-O— and “substitutedheterocyclyloxy refers to the group substituted heterocyclyl-O— whereheterocyclyl and substituted heterocyclyl are defined above.

“Cycloalkylthio” refers to the group —S-cycloalkyl and “substitutedcycloalkylthio” refers to the group —S-substituted cycloalkyl, wherecycloalkyl and substituted cycloalkyl are defined above.

“Biological activity” as used herein refers to an inhibitionconcentration when tested in at least one of the assays outlined in anyof Examples 13-15.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds offormulas I and II. These salts can be prepared in situ during the finalisolation and purification of the compounds of formulas I and II, or byseparately reacting the base or acid functions with a suitable organicor inorganic acid or base, respectively. Representative salts include,but are not limited to, the following: acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemi-sulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-napth-alenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate,succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as alkyl halides, such as methyl, ethyl,propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formulas I and II,or separately by reacting carboxylic acid moieties with a suitable basesuch as the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation or with ammonia, or an organic primary,secondary or tertiary amine. Pharmaceutically acceptable salts include,but are not limited to, cations based on the alkali and alkaline earthmetals, such as sodium, lithium, potassium, calcium, magnesium, aluminumsalts and the like, as well as ammonium, quaternary ammonium, and aminecations, including, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methyl amine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like. Other representative organicamines useful for the formation of base addition salts includediethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazineand the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down in thehuman body to leave the parent compound, a salt thereof, or apharmaceutically active metabolite. Suitable ester groups include, forexample, those derived from pharmaceutically acceptable aliphaticcarboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic andalkanedioic acids, in which each alkyl or alkenyl moiety advantageouslyhas not more than 6 carbon atoms. Representative examples of particularesters include, but are not limited to, formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrug” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound or a pharmaceuticallyactive metabolite of the above formula, for example by hydrolysis inblood. A discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

As used herein “anticancer agents” or “agent for the treatment ofcancer” refers to agents that include, by way of example only, agentsthat induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides(e.g., enzymes); drugs; biological mimetics; alkaloids; alkylatingagents; antitumor antibiotics; antimetabolites; hormones; platinumcompounds; monoclonal antibodies conjugated with anticancer drugs,toxins, and/or radionuclides; biological response modifiers (e.g.interferons and interleukins, etc.); adoptive immunotherapy agents;hematopoietic growth factors; agents that induce tumor celldifferentiation (e.g. all-trans-retinoic acid, etc.); gene therapyreagents; antisense therapy reagents and nucleotides; tumor vaccines;inhibitors of angiogenesis, and the like. Numerous other agents are wellwithin the purview of one of skill in the art.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. In such cases, the maximumnumber of such substituents is three. That is to say that each of theabove definitions is constrained by a limitation that, for example,substituted aryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups or a hydroxy group alpha to ethenylic or acetylenicunsaturation). Such impermissible substitution patterns are well knownto the skilled artisan.

Compounds of this invention may exhibit stereoisomerism by virtue of thepresence of one or more asymmetric or chiral centers in the compounds.The present invention contemplates the various stereoisomers andmixtures thereof. Depiction of the compounds of Formulas I and IIincludes the stereoisomers thereof. Certain of the compounds of theinvention comprise asymmetrically substituted carbon atoms. Suchasymmetrically substituted carbon atoms can result in the compounds ofthe invention comprising mixtures of stereoisomers at a particularasymmetrically substituted carbon atom or a single stereoisomer. As aresult, racemic mixtures, mixtures of diastereomers, single enantiomer,as well as single diastereomers of the compounds of the invention areincluded in the present invention. The terms “S” and “R” configuration,as used herein, are as defined by the IUPAC 1974 “RECOMMENDATIONS FORSECTION E, FUNDAMENTAL STEREOCHEMISTRY ,” Pure Appl. Chem. 45:13-30,1976. Desired enantiomers can be obtained by chiral synthesis fromcommercially available chiral starting materials by methods well knownin the art, or may be obtained from mixtures of the enantiomers byseparating the desired enantiomer by using known techniques.

Compounds of this invention may also exhibit geometrical isomerism.Geometrical isomers include the cis and trans forms of compounds of theinvention having alkenyl or alkenylenyl moieties. The present inventioncomprises the individual geometrical isomers and stereoisomers andmixtures thereof.

C. Compound Preparation

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.Unless otherwise indicated, the starting materials are commerciallyavailable and well known in the art. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures) are given, otherprocess conditions can also be used unless otherwise stated. Optimumreaction conditions may vary with the particular reactants or solventused, but such conditions can be determined by one skilled in the art byroutine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Second Edition, Wiley, New York, 1991, and referencescited therein.

Furthermore, the compounds of this invention may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers, or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

Compounds in the present invention may be better understood by thefollowing synthetic Scheme that illustrate methods for the synthesis ofcompounds of the invention. Unless otherwise indicated, the reagentsused in the following examples are commercially available and may bepurchased from vendors such as Sigma-Aldrich Company, Inc. (Milwaukee,Wis., USA).

As discussed above, compounds of the invention have the followingstructure:

where R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as defined herein and R^(5′) is—CH₂—R⁵ (provided that R⁵ is not hydrogen) where R⁵ is as definedherein.

Step A: Keto-Ester Synthesis

PG refers to a suitable nitrogen protecting group such as BOC.

Specifically, in Step A, an appropriately protected (PG) amino acid 1a,is dissolved in a suitable amount of an inert solvent such as methanolor ethanol. It should be noted that amino acid 1a, is typicallycommercially available as are α,α-disubstituted amino acids(PG-NH—C(R¹)(R²)—COOH). To that is added a stoichiometric amount of amonovalent cation, such as cesium carbonate (Cs₂CO₃) or potassiumcarbonate (K₂CO₃), to form the carboxylate salt (not shown). Uponsubstantial completion of the reaction, typically about 15 minutes toabout 2 hours, excess solvent is removed by evaporation under reducedpressure. The residual cesium or potassium salt is then re-dissolved ina suitable solvent, such as DMF and then treated with one to fourequivalents of the appropriate α-halo-ketone 1b (1 eq.), e.g.,2-bromoacetophenone and stirred at RT until the reaction issubstantially complete.

The product 1c is then recovered by conventional methods such asextraction, filtration, evaporation, and the like. It is generally pureenough to use directly in the next step.

Step B: Imidazole Formation

To a stirred solution of keto-ester 1c from step A in a suitable amountof inert solvent, such as xylenes, is added an excess of ammoniumacetate, typically from about 2 to about 20 equivalents and preferablyabout 5 equivalents. In one embodiment, a Dean-Stark trap is added andthe reaction mixture is heated to about 120° C. to about 160° C. untilthe reaction is substantially complete. In another embodiment, thereactants are refluxed in toluene. Once the reaction is substantiallycomplete, the mixture is allowed to cool to RT. The product, imidazole1d, is then recovered by conventional methods such as extraction,filtration, evaporation, and the like. It is generally pure enough touse directly in the next step.

Step C: N-Alkylation of the Imidazole

The imidazole 1d is then reacted with an appropriate aryl orheteroaryl-substituted alkyl halide, such as benzyl bromide. Typically,this can be accomplished by stirring the imidazole 1d with an excess ofpotassium carbonate and DMF and then adding at least an equimolar amountof the aryl or heteroaryl-substituted alkyl halide. Once the reaction issubstantially complete, the N-alkyl imidazole 1e is recovered byconventional methods such as extraction, filtration, evaporation,recrystallization, and the like.

Compounds of the invention when R⁸ is L-A¹ and L is —S(O)_(q)— may besynthesized using a suitable sulfonyl chloride. Descriptions of varioussulfonyl chlorides may be found, for example, U.S. Pat. No. 6,489,300,which is hereby incorporated by reference.

In either case, imidazole 1e is used in the Step D below.

Step D: Deprotection to the free amine

The protecting group, PG is then removed by conventional techniques toprovide amine if, which is then optionally purified by conventionalmethods such as extraction, filtration, evaporation, and the like. Theamine if is used directly in the next step.

Step E: Reductive Amination

Amine 1f then undergoes conventional reductive amination with anappropriate aldehyde 1g to yield substituted amine 1h which is thenrecovered and optionally purified by conventional methods such asextraction, filtration, evaporation, chromatography, and the like.

In embodiments where R⁵ is hydrogen, Steps D and E may be skipped. Inthese embodiments, imidazole 1e is used in Step F to make the suitablecarbamate.

Step F: Carbamate Formation

The substituted amine 1h from step E is then put into a solution with asuitable solvent such as methylene chloride and an excess of a suitablebase, such as triethylamine. Then a suitable carbamate-forming agent,such as triphosgene as shown is added to form carbamate 1i. Once thereaction is complete, the carbamate 1i is recovered by conventionalmethods such as extraction, filtration, evaporation, and the like. Thecarbamate 1i is used directly in the next step or may be optionallypurified by conventional techniques.

Step G: Urea Formation

Carbamate 1i from step F is then combined with a slight excess of theappropriate amine 1p to form the urea 1j. Once the reaction is complete,the product 1j is recovered by conventional methods such as extraction,filtration, evaporation, and the like.

It will be well within the skill of the art to further modify the abovepreparation to synthesize other compounds of the invention. For example,reaction of suitable isocyanate with amine 1h provides for ureacompounds as illustrated, e.g., in Example 3.

D. Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of the subject inventionare usually administered in the form of pharmaceutical compositions.These compositions can be administered by a variety of routes includingoral, parenteral, transdermal, topical, rectal, and intranasal. Thesecompounds are effective, for example, as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the subjectinvention above associated with pharmaceutically acceptable carriers. Inmaking the compositions of this invention, the active ingredient isusually mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier which can be in the form of a capsule, sachet,paper or other container. The excipient employed is typically anexcipient suitable for administration to human subjects or othermammals. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g., about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The quantity of active component, that is the compound according to thesubject invention, in the pharmaceutical composition and unit dosageform thereof may be varied or adjusted widely depending upon theparticular application, the potency of the particular compound and thedesired concentration.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, usually about 5 to about100 mg, occasionally about 10 to about 30 mg, of the active ingredient.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Preferably, the compound of thesubject invention above is employed at no more than about 20 weightpercent of the pharmaceutical composition, more preferably no more thanabout 15 weight percent, with the balance being pharmaceutically inertcarrier(s).

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically or therapeuticallyeffective amount. It will be understood, however, that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the severity of the condition being treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

In therapeutic use for treating, or combating, cancer in mammals, thecompounds or pharmaceutical compositions thereof will be administered byany appropriate route, such as orally, topically, transdermally, and/orparenterally at a dosage to obtain and maintain a concentration, thatis, an amount, or blood-level of active component in the mammalundergoing treatment that will be therapeutically effective. Generally,such therapeutically effective amount of dosage of active component(i.e., an effective dosage) will be in the range of about 0.1 to about100, more preferably about 1.0 to about 50 mg/kg of body weight/day.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as corn oil,cottonseed oil, sesame oil, coconut oil, or peanut oil, as well aselixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following formulation examples illustrate representativepharmaceutical compositions of the present invention.

Formulation Example 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation Example 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

Formulation Example 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Formulation Example 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Example 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, starch and magnesium stearate are blended, passedthrough a No. 20 mesh U.S. sieve, and filled into hard gelatin capsulesin 150 mg quantities.

Formulation Example 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7

Suspensions, each containing 50 mg of medicament per 5.0 mL dose aremade as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Formulation Example 8

Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 425.0 mg quantities.

Formulation Example 9

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Formulation Example 10

A topical formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g LiquidParaffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Formulation Example 11

An intravenous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 250 mg Isotonic saline 1000 mL

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa., 17th ed. (1985).

E. Dosage and Administration

As noted above, the compounds described herein are suitable for use in avariety of drug delivery systems described above. Additionally, in orderto enhance the in vivo serum half-life of the administered compound, thecompounds may be encapsulated, introduced into the lumen of liposomes,prepared as a colloid, or other conventional techniques may be employedwhich provide an extended serum half-life of the compounds. A variety ofmethods are available for preparing liposomes, as described in, e.g.,Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each ofwhich is incorporated herein by reference.

Compounds of the instant invention are useful for inhibiting or treatinga disorder mediated, at least in part, by the activity of KSP. In oneaspect, the disorder that is mediated, at least in part by KSP, is acellular proliferative disorder. The term “cellular proliferativedisorder” or “cell proliferative disorder” refers to diseases including,for example, cancer, tumor, hyperplasia, restenosis, cardiachypertrophy, immune disorder and inflammation. The present inventionprovides methods of treating a human or mammalian subject in need ofsuch treatment, comprising administering to the subject atherapeutically effective amount of a compound of formula I or II,either alone or in combination with other anticancer agents.

The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The term “cancer” refers tocancer diseases including, for example, lung and bronchus; prostate;breast; pancreas; colon and rectum; thyroid; stomach; liver andintrahepatic bile duct; kidney and renal pelvis; urinary bladder;uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus;acute myelogenous leukemia; chronic myelognous leukemia; lymphocyticleukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx;small intestine; non-hodgkin lymphoma; melanoma; and villous colonadenoma.

Cancer also includes tumors or neoplasms selected from the groupconsisting of carcinomas, adenocarcinomas, sarcomas, and hematologicalmalignancies.

Additionally, the type of cancer can be selected from the groupconsisting of growth of solid tumors/malignancies, myxoid and round cellcarcinoma, locally advanced tumors, human soft tissue carcinoma, cancermetastases, squamous cell carcinoma, esophageal squamous cell carcinoma,oral carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producingtumors, nonsmall cell cancers, breast cancer, gastrointestinal cancers,urological cancers, malignancies of the female genital tract,malignancies of the male genital tract, kidney cancer, brain cancer,bone cancers, skin cancers, thyroid cancer, retinoblastoma,neuroblastoma, peritoneal effusion, malignant pleural effusion,mesothelioma, Wilms's tumors, gall bladder cancer, trophoblasticneoplasms, hemangiopericytoma, and Kaposi's sarcoma.

A compound or composition of this invention may be administered to amammal by a suitable route, such as orally, intravenously, parenterally,transdermally, topically, rectally, or intranasally.

Mammals include, for example, humans and other primates, pet orcompanion animals, such as dogs and cats, laboratory animals, such asrats, mice and rabbits, and farm animals, such as horses, pigs, sheep,and cattle.

Tumors or neoplasms include growths of tissue cells in which themultiplication of the cells is uncontrolled and progressive. Some suchgrowths are benign, but others are termed “malignant” and can lead todeath of the organism. Malignant neoplasms or “cancers” aredistinguished from benign growths in that, in addition to exhibitingaggressive cellular proliferation, they can invade surrounding tissuesand metastasize. Moreover, malignant neoplasms are characterized in thatthey show a greater loss of differentiation (greater“dedifferentiation”) and organization relative to one another and tosurrounding tissues. This property is called “anaplasia.”

Compounds having the desired biological activity may be modified asnecessary to provide desired properties such as improved pharmacologicalproperties (e.g., in vivo stability, bio-availability), or the abilityto be detected in diagnostic applications. Stability can be assayed in avariety of ways such as by measuring the half-life of the compoundsduring incubation with peptidases or human plasma or serum.

For diagnostic purposes, a wide variety of labels may be linked to thecompounds, which may provide, directly or indirectly, a detectablesignal. Thus, the compounds and/or compositions of the subject inventionmay be modified in a variety of ways for a variety of end purposes whilestill retaining biological activity. In addition, various reactive sitesmay be introduced for linking to particles, solid substrates,macromolecules, and the like.

Labeled compounds can be used in a variety of in vivo or in vitroapplications. A wide variety of labels may be employed, such asradionuclides (e.g., gamma-emitting radioisotopes such as technetium-99or indium-111), fluorescers (e.g., fluorescein), enzymes, enzymesubstrates, enzyme cofactors, enzyme inhibitors, chemiluminescentcompounds, bioluminescent compounds, and the like. Those of ordinaryskill in the art will know of other suitable labels for binding to thecomplexes, or will be able to ascertain such using routineexperimentation. The binding of these labels is achieved using standardtechniques common to those of ordinary skill in the art.

Pharmaceutical compositions of the invention are suitable for use in avariety of drug delivery systems. Suitable formulations for use in thepresent invention are found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

The amount administered to the patient will vary depending upon what isbeing administered, the purpose of the administration, such asprophylaxis or therapy, the state of the patient, the manner ofadministration, and the like. In therapeutic applications, compositionsare administered to a patient already suffering from a disease in anamount sufficient to cure or at least partially arrest the progressionor symptoms of the disease and its complications. An amount adequate toaccomplish this is defined as “therapeutically effective dose.” Amountseffective for this use will depend on the disease condition beingtreated as well as by the judgment of the attending clinician dependingupon factors such as the severity of the disease, disorder or condition,the age, weight and general condition of the patient, and the like.

The compounds administered to a patient are typically in the form ofpharmaceutical compositions described above. These compositions may besterilized by conventional sterilization techniques, or may be sterilefiltered. The resulting aqueous solutions may be packaged for use as is,or lyophilized, the lyophilized preparation being combined with asterile aqueous carrier prior to administration. The pH of the compoundpreparations typically will be between about 3 and 11, more preferablyfrom about 5 to 9 and most preferably from about 7 to 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds and/or compositions of thepresent invention will vary according to, for example, the particularuse for which the treatment is made, the manner of administration of thecompound, the health and condition of the patient, and the judgment ofthe prescribing physician. For example, for oral administration, thedose will typically be in the range of about 5 μg to about 50 mg perkilogram body weight per day, preferably about 1 mg to about 10 mg perkilogram body weight per day. In the alternative, for intravenousadministration, the dose will typically be in the range of about 5 μg toabout 50 mg per kilogram body weight, preferably about 500 μg to about5000 μg per kilogram body weight. Alternative routes of administrationcontemplated include, but are not limited to, intranasal, transdermal,inhaled, subcutaneous and intramuscular. Effective doses can beextrapolated from dose-response curves derived from in vitro or animalmodel test systems.

In general, the compounds and/or compositions of the subject inventionwill be administered in a therapeutically effective amount by any of theaccepted modes of administration for agents that serve similarutilities. Toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD₅₀ (the dose lethal to50% of the population) and the ED₅₀ (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices arepreferred.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compoundand/or composition used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays. A dose may be formulated in animal models to achieve acirculating plasma concentration range which includes the IC₅₀ (theconcentration of the test compound which achieves a half-maximalinhibition of activity) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsin plasma may be measured, for example, by high performance liquidchromatography.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods, which are well known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Millenniumchromatography system with a 2690 Separation Module (Milford, Mass.).The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm fromAlltech (Deerfield, Ill.). A gradient elution was used, typicallystarting with 5% acetonitrile/95% water and progressing to 100%acetonitrile over a period of 40 minutes. All solvents contained 0.1%trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light(UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdickand Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburgh, Pa.).In some instances, purity was assessed by thin layer chromatography(TLC) using glass or plastic backed silica gel plates, such as, forexample, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results werereadily detected visually under ultraviolet light, or by employing wellknown iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two LC/MSinstruments: a Waters System (Alliance HT HPLC and a Micromass ZQ massspectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; solvent system: 5-95%(or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA;flow rate 0.8 mL/min; molecular weight range 500-1500; cone Voltage 20V; column temperature 40° C.) or a Hewlett Packard System (Series 1100HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; solvent system: 1-95%acetonitrile in water with 0.05% TFA; flow rate 0.4 mL/min; molecularweight range 150-850; cone Voltage 50 V; column temperature 30° C.). Allmasses were reported as those of the protonated parent ions.

GC/MS analysis is performed on a Hewlett Packard instrument (HP6890Series gas chromatograph with a Mass Selective Detector 5973; injectorvolume: 1 mL; initial column temperature: 50° C.; final columntemperature: 250° C.; ramp time: 20 minutes; gas flow rate: 1 mL/min;column: 5% phenyl methyl siloxane, Model No. HP 190915-443, dimensions:30.0 m×25 m×0.25 m).

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 300 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.Some compound samples were run at elevated temperatures (e.g., 75° C.)to promote increased sample solubility.

The purity of some of the invention compounds is assessed by elementalanalysis (Desert Analytics, Tucson, Ariz.).

Melting points are determined on a Laboratory Devices MeI-Temp apparatus(Holliston, Mass.).

Preparative separations were carried out using a Flash 40 chromatographysystem and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flashcolumn chromatography using silica gel (230-400 mesh) packing material,or by HPLC using a C-18 reversed phase column. Typical solvents employedfor the Flash 40 Biotage system and flash column chromatography weredichloromethane, methanol, EtOAc, hexane, acetone, aqueous hydroxyamineand triethyl amine. Typical solvents employed for the reverse phase HPLCwere varying concentrations of acetonitrile and water with 0.1%trifluoroacetic acid.

Unless otherwise stated all temperatures are in degrees Celsius. Also,in these examples and elsewhere, abbreviations have the followingmeanings:

AcOH = acetic acid aq. = aqueous ATP = adenosine triphosphate Boc =tert-butyloxycarbonyl BSA = bovine serum albumin CAM = ceric ammoniummolybdate DCM = dichloromethane DIAD = diisopropyl azodicarboxylateDIBAL = diisobutylaluminum hydride DIEA = diisopropylethylamine DIPEA =diisopropylethylamine DMAP = dimethylaminopyridine DMF =dimethylformamide DMSO = dimethylsulfoxide DTT = dithiothreitol eq. =equivalents Et₂O diethyl ether Et₃N = triethyl amine EtOAc = ethylacetate EtOH = ethanol g = gram h = hour HPLC = high performance liquidchromatography L = liter LC/MS = liquid chromatography/mass spectroscopyM = molar m = meter m/z = mass/charge ratio MeNH₂ = methyl amine mg =milligram min = minute mL = milliliter mm = millimeter mM = millimolarmmol = millimole mol = mole N = normal nm = nanometer nM = nanomolar NMR= nuclear magnetic resonance PPh₃ = triphenyl phosphine PhCF₃ =trifluoromethylbenzene psi = pounds per square inch RT = roomtemperature sat. = saturated TEA = triethylamine THF = tetrahydrofuranTFA = trifluoroacetic acid TLC = thin layer chromatography TMS =trimethylsilyl TMSCl = trimethylsilyl chloride μg = microgram μL =microliter μM = micromolar

Example 1 Preparation ofN-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S)-3-fluoropyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide(76) andN-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3R)-3-fluoropyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide(77) Step A: Keto Ester Synthesis

A stirred 0.4 M solution of the appropriate N-Boc-acid (1 eq.), e.g.,tert-butyl leucine 1-1 in EtOH, was treated with Cs₂CO₃ (0.5 eq.). After45 min, the EtOH was removed by evaporation under reduced pressure. Theresidual cesium salt was re-dissolved in DMF (1.5× volume of DMF used inthe reaction) and then treated with the appropriate α-halo-ketone, e.g.,2-bromoacetophenone (1 eq.) and stirred at RT until the reaction wascomplete. The reaction mixture was then partitioned between EtOAc andH₂O, and the organics separated, then washed with H₂O (×3), brine (×3),then dried (Na₂SO₄), filtered, and evaporated under reduced pressure togive the keto ester 1-2 which was pure enough to use directly in thenext step.

Step B: Phenyl Imidazole Formation

To a stirred 0.1 M solution of keto-ester 1-2 (1 eq.) in xylenes wasadded ammonium acetate (5 eq.). A Dean-Stark trap was added and thereaction heated to 140° C. Once the reaction was complete, the mixturewas allowed to cool to RT, then partitioned between EtOAc and sat. aq.NaHCO₃. The organics were separated, then washed with sat. aq. NaHCO₃(×2), H₂O (×3), brine (×3), then dried (Na₂SO₄), filtered, andevaporated under reduced pressure to give the phenyl imidazole 1-3 whichwas pure enough to use directly in the next step.

Step C: Benzylation of the Phenyl Imidazole

To a stirred 0.4 M solution/suspension of imidazole 1-3 (1 eq.) in DMFwas added K₂CO₃ (2 eq.) and the benzylating agent, e.g., benzyl bromide(1.1 eq.). Once the reaction was complete, the mixture was partitionedbetween EtOAc and H₂O. The organic layer was separated and washed withH₂O (×3), brine (×3), then dried (Na₂SO₄), filtered, and evaporatedunder reduced pressure to give the crude benzylated phenyl imidazole.The crude reaction material was then crystallized (EtOAc, hexanes) togive pure product 1-4.

Step D: Deprotection to the Free Amine

Boc-protected amine 1-4 was treated with 10% TFA in DCM. Once reactionwas complete, the reaction mixture was concentrated in vacuo and thenpartitioned between EtOAc and sat. aq. NaHCO₃. The organics wereseparated, then washed with sat. aq. NaHCO₃ (×2), H₂O (×2), brine (×2),then dried (Na₂SO₄), filtered, and evaporated under reduced pressure togive the phenyl imidazole free amine 1-5 which was pure enough to usedirectly in the next step.

Step E: Preparation of Racemic Aldehyde 1-8

A mixture of 0.83 M solution of N-Boc-3-formyl pyrrolidine 1-6 (1 eq.)in DMF, TMSCl (2.5 eq.) and Et₃N (5 eq.) was heated for 6 h. The mixturewas then diluted with hexanes and filtered (Celite). The filtrate wasthen evaporated under reduced pressure to give the TMS enol ethers 1-7as a mixture of E and Z isomers that were used directly in the nextstep.

To a 0.1 M solution of TMS enol ether 1-7 (1 eq.) in CH₃CN was addedSelectFluor® (1.1 eq., available from Sigma-Aldrich). Once the reactionwas complete, the mixture was evaporated under reduced pressure and theremaining solid/oil was extracted with Et₂O (×5). The ether extractswere evaporated under reduced pressure to give the crude aldehyde.Purification by silica gel chromatography afforded the desired aldehyde1-8.

Step F: Reductive Amination

To a stirred 0.1 M solution of (R)-amine 1-5 (1 eq.) from step D in DCM,was added aldehyde 1-8 (1.1 eq.) followed by AcOH (1 eq.) followed bysodium tris-acetoxyborohydride (1.5 eq.). After 19 h, further sodiumtris-acetoxyborohydride (0.5 eq.) was added. Once the reaction wascomplete, the mixture was concentrated in vacuo, partitioned betweenEtOAc and 1M NaOH. The organics were separated, then washed with 1M NaOH(×2), H₂O (×1), brine (×2), then dried (Na₂SO₄), filtered, andevaporated under reduced pressure to give crude product. Purification bysilica gel chromatography afforded the amine 1-9 as a mixture of (R,R)and (R,S) diastereomers.

Step G: Trichlorocarbamate Formation

To a 0.08 M solution of (R) amine 1-9 from step F (1 eq.) in DCM wasadded Et₃N (4 eq.) followed by triphosgene (1.2 eq.). Once the reactionwas complete, the reaction mixture was concentrated in vacuo,partitioned between EtOAc and sat. aq. NaHCO₃. The organics wereseparated, then washed with sat. aq. NaHCO₃ (×2), H₂O (×1), brine (×2),then dried (Na₂SO₄), filtered, and evaporated under reduced pressure togive crude trichlorocarbamate 1-10 which was used directly in the nextstep.

Step H: Urea Formation

To a stirred 0.16 M solution of trichlorocarbamate 1-10 from step G (1eq.) in DCM was added DIPEA (5 eq.) followed by 4-piperidinopiperidine(3 eq.). Once the reaction was complete, the mixture was concentrated invacuo, partitioned between EtOAc and sat. aq. NaHCO₃. The organics wereseparated, then washed with sat. aq. NaHCO₃ (×2), H₂O (×1), brine (×2),then dried (Na₂SO₄), filtered, and evaporated under reduced pressure togive crude product as a mixture of 1-11 and 1-12. This was purified byreverse phase prep. HPLC which separated the (R,R) and the (R,S)diastereomers 1-11 and 1-12.

Step I: Final Deprotection to Compound 76 and 77

Boc-protected amine 1-11 was treated with 10% TFA/DCM. Once reaction wascomplete, the reaction mixture was evaporated under reduced pressure togive the title compound that was purified by reverse phase prep. HPLC togive the pure 76. Compound 77 (not shown here) was synthesized using theother isomer 1-12 from step H.

Example 2 Preparation ofN-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-1-carboxamide(26) Step A: Reductive Amination

The phenyl imidazole 1-5 from step D of Example 1 (1 eq., 2.0 g) wascombined with the aldehyde (1.3 eq., 1.56 g) and sodiumtriacetoxyborohydride (2 eq., 2.65 g) in 30 mL of methylene chloride.This was followed by acetic acid (2 eq., 0.72 mL) and the reaction wasstirred at RT under nitrogen overnight. The reaction was worked up withwater, saturated sodium bicarbonate then saturated sodium chloride. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated. The material was purified on a column and gave theresulting product 2-1 as 2.15 g of a white solid.

Step B: Trichlorocarbamate Formation

The phenyl imidazole amine 2-1 (1 eq., 100 mg) was dissolved in 4 mL oftetrahydrofuran and cooled down to 0° C. Triphosgene (1.7 eq., 102 mg)was added to the solution followed by triethylamine (6 eq., 169 mL). Thereaction was stirred for 2 h and allowed to warm up to RT. The solventwas evaporated and the material dissolved in EtOAc and worked up asfollows: water, saturated sodium bicarbonate and saturated sodiumchloride. The organic layer was dried over magnesium sulfate, filteredand dried resulting in 133 mg of the trichlorocarbamate 2-2.

Step C: Urea Formation

The trichlorocarbamate 2-2 (1 eq., 133 mg) from step B above was reactedwith piperazine (10 eq., 175 mg) by stirring in 4 mL of tetrahydro furanat RT for 2 h. The solvent was evaporated and the material redissolvedin EtOAc and washed with saturated sodium bicarbonate and saturatedsodium chloride. The organic layer was dried over magnesium sulfate,filtered and concentrated resulting in 115 mg of the urea as a mixtureof two isomers. The isomers were separated by purification, only isomer2-3 is shown here.

Step D: Final Deprotection to 25 and 26

The Boc protected urea 2-3 from step C above (1 eq., 18 mg) was treatedwith 1 mL of 20% trifluoroacetic acid in methylene chloride at RT for 2h. The solvent was evaporated to give the final product 26. Compound 25was synthesized using the other isomer from step C.

Example 3 Preparation ofN-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(4-cyanophenyl)urea(64) Step A: Urea Formation

The phenyl imidazole amine 2-1 (1 eq., 15 mg) from Step A of Example 2was reacted with 4-cyanophenyl isocyanate (10 eq., 44 mg) in 1 mL oftetrahydrofuran at 60° C. overnight. The solvent was evaporated and thematerial dissolved in EtOAc and washed with water, saturated sodiumbicarbonate and saturated sodium chloride. The organic layer was driedover magnesium sulfate, filtered and dried. The Boc was deprotectedfollowing step D in Example 2.

Example 4 Preparation of1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]tetrahydropyrimidin-2(1H)-one(52) Step A: Reductive Amination

To a stirred solution of amine 1-5 from Step D of Example 1(1.0 eq.) inDCM was added appropriate aldehyde (1.0 eq.). The mixture was allowed tostir for 5 min before the addition of sodium tris-acetoxyborohydride(1.0 eq.). Once the reaction was complete, the mixture was concentratedin vacuo, partitioned between EtOAc and 2M aq. Na₂CO₃. The organics wereseparated, then washed with 2M aq. Na₂CO₃ (×2), H₂O (×2), brine (×2),then dried (Na₂SO₄), filtered, and evaporated under reduced pressure togive product 4-1 which was used directly in the next step.

Step B: Carbamoyl Chloride Formation

To a 50 mL flask was added 1.97 mL of 20% phosgene (10 eq.) in toluene.To that was added a solution of product 4-1 from Step A (200 mg, 1 eq.)in dry DCM (3 mL) and triethylamine (0.517 mL, 10 eq.). The reactionmixture was stirred at RT for about 10 min. After the completion of thereaction, the mixture was diluted in DCM, washed with water, brine,dried (Na₂SO₄), filtered, and evaporated under reduced pressure.Purification on silica gel to afford 180 mg of carbamoyl chloride 4-2 aswhite solid.

Step C: Urea Formation

To a stirred solution of carbamoyl chloride 4-2 from step B (1 eq.) inDMF was added 3-amino-1,2,4-triazole (2 eq.), Et₃N (2 eq.) and DMAP (1eq.). The reaction was stirred at RT and progress was monitored byLC/MS. After completion, the solvent was evaporated under reducedpressure. The crude product was dissolved in ethanol and hydrazine wasadded. The reaction was stirred at RT. After completion, the solvent wasevaporated under reduced pressure and portioned between EtOAc and water.The organics were separated, then washed with 2 M aq. Na₂CO₃ (×2), H₂O(×2), brine (×2), then dried (Na₂SO₄), filtered, and evaporated underreduced pressure. Purification by reverse phase prep. HPLC afforded 52.MS: m/z 403.2

Example 5 Preparation ofN-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide(83) andN-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S,4S)-4-hydroxypyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide(84) Step A: Epoxidation

To a 100 mL round bottom flask was added 5.0 g (29.5 mmol)2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester, 11.7 g (67.9mmol) 3-chloroperoxybenzoic acid, and 70 mL of DCM. The mixture wasstirred at ambient temperature under nitrogen for 20 h. Excess 1N NaOHwas then added and the reaction mixture was extracted with DCM (×3). Theproduct was determined by thin layer chromatography (4:1 hexanes:EtOAc)using ninhydrin stain. The organic layers were combined, dried overMgSO₄, and the solvent was removed in vacuo yielding 5.1974 g (28.1mmol, 95%) of product 5-1 as a yellow oil.

Step B: Vinylation

To a dry 200 mL round bottom flask was added 4.31 g (23.3 mmol) product5-1 from step A, 0.21 g (2.33 mmol) copper cyanide, and 50 mL anhydrousTHF and the resulting solution was cooled to −78° C. To the reactionmixture was then added dropwise 73.3 mL (73.3 mmol) vinylmagnesiumbromide and the resulting solution was allowed to warm slowly to ambienttemperature under nitrogen over the course of 7 h. The reaction mixturewas quenched with saturated NH₄Cl and extracted with EtOAc (×3). Theproduct was determined by thin layer chromatography (2:1 hexanes:EtOAc)using ninhydrin stain. The organic layers were combined, dried overMgSO₄, and the solvent was removed in vacuo yielding 4.75 g product 5-2as a tan oil.

Step C: Oxidation

To a solution of 2.0 g (9.4 mmol) of product 5-2 from step B in 30 mL ofTHF and 15 mL of H₂O, was added 3.5 g (16.4 mmol) of NaIO₄ and 0.23 mL(0.94 mmol) of OSO₄. Formation of a white precipitate was observed afterapproximately 30 minutes. The reaction was monitored by thin layerchromatography (1:1 hexanes:EtOAc) using ninhydrin stain. Stirringcontinued for an additional 7 h at ambient temperature under nitrogenand the reaction was then quenched with H₂O and extracted with EtOAc(×3). The organic layers were combined, washed with saturated NaHCO₃ andbrine, dried over MgSO₄, and the solvent was removed in vacuo yielding1.35 g (6.3 mmol, 67%) product 5-3 as a tan foam.

Step D: Reductive Amination

To a dry 100 mL round bottom flask was added 1.6 g (5.0 mmol) ofphenylimidazole free amine 1-5 from step D of Example 1, 1.35 g (6.26mmol) of product-5-3 from step C above, 1.38 g (6.5 mmol) sodiumtris-acetoxyborohydride, 25 mL anhydrous DCM, and 0.37 mL (6.5 mmol)acetic acid. The resulting solution was stirred at ambient temperatureunder nitrogen for 2 h. Excess DCM was then added to the reactionmixture. The organic layer was washed with H₂O, saturated NaHCO₃ (×2),and brine (×2). The combined organic layers were dried over MgSO₄ andthe solvent was removed in vacuo. The resulting crude material wassubjected to flash column chromatography and the product was eluted witha gradient of hexanes, 20% EtOAc in hexanes, 50% EtOAc in hexanes, and10% methanol and 0.3% ammonia in DCM yielding 1.56 g (3.0 mmol, 60%)product 5-4 as a tan foam. Product 5-4 was provided as a mixture ofdiastereomers.

MH+=519.3

Step E: Protection

To a 25 mL round bottom flask was added 0.2 g (0.39 mmol) product 5-4from step D, 0.04 g (0.56 mmol) imidazole, 0.08 g (0.56 mmol)tert-butylchlorodimethylsilane, 0.005 g (0.04 mmol) DMAP, and 3 mL DMF.The resulting solution was stirred at ambient temperature under nitrogenfor 24 h. The reaction was quenched with H₂O and extracted with EtOAc(×3). The combined organic layers were washed with saturated NaHCO₃ andbrine, dried over MgSO₄, and the solvent was removed in vacuo yielding0.28 g (0.44 mmol, 113%) product 5-5 as a crude tan oil. MH+=633.3

Step F: Trichlorocarbamate Formation

To a solution of 0.05 g (0.08 mmol) product 5-5 from step E in 1 mL ofanhydrous THF at 0° C., was added 0.04 g (0.14 mmol) triphosgene and0.07 mL (0.48 mmol) triethylamine. The mixture was stirred at 0° C. for1 h. The reaction was monitored by TLC (4:1 hexanes:EtOAc). After thecompletion of the reaction, H₂O was added and it was extracted withEtOAc (×2). The combined organic layers were washed with saturatedNaHCO₃ and brine, dried over MgSO₄, and the solvent was removed in vacuoyielding 0.08 g (0.10 mmol, 125%) product 5-6 as a crude tan oil.

Step G: Urea Formation

To a dry reaction vial was added 0.08 g (0.1 mmol) product 5-6 form stepF, 0.17 g (1.0 mmol) 4-piperidinopiperidine, and 1.5 mL anhydrous THF.The resulting solution was stirred at ambient temperature for 20 h. Thereaction was then quenched with H₂O and extracted with EtOAc (×3). Thecombined organic layers were washed with H₂O, saturated NaHCO₃ andbrine, dried over MgSO₄, and the solvent was removed in vacuo yielding0.06 g (0.07 mmol, 73%) product 5-7 as a crude tan oil. MH+=827.5

Step H: Deprotection

To a reaction vial was added 0.028 g (0.03 mmol) product 5-7 from step Gand 0.5 mL THF and the resulting solution was cooled to 0° C. To thereaction mixture was then added 0.05 g (0.17 mmol) tetrabutylammoniumfluoride and the reaction was allowed to warm to ambient temperatureover 1 h. The reaction was then quenched with saturated NH₄Cl, extractedwith EtOAc (×3), and the combined organic layers were dried over MgSO₄,and the solvent was removed in vacuo yielding 0.05 g (0.07 mmol, 213%)product 5-8 as a crude tan/yellow foam. MH+=713.4

Step I: Deprotection

To a reaction vial was added 0.05 g (0.07 mmol) product 5-8 from step H,1.0 mL DCM, and 0.1 mL TFA and the resulting solution was shaken atambient temperature for 2 h. The solvent was then removed in vacuo andthe crude reaction material was purified by reverse phase HPLC yielding3.8 mg (0.006 mmol, 9%) 83 as a white TFA salt and 4.6 mg (0.008 mmol,11%) 84 (other diastereomer not shown here) as a white TFA salt. MH+ of83=613.4 and MH+ of 84=613.3

Example 6 Preparation for Intermediate of β-Fluoro Aldehyde Side Chain(6-7)

Step A: Amine Protection

To a stirred solution of anhydrous K₂CO₃ (46.53 g, 0.3371 mol) in DMF(500 mL), D-serine methyl ester hydrochloride (35.0 g, 0.2250 mol), KI(18.66 g, 0.1124 mol) and benzyl bromide (96.18 g, 0.5623 mol) wereadded in one shot. The reaction mixture was stirred vigorously for 5 hat RT. After completion of the reaction, the contents were poured intoice water and extracted with EtOAc. The combined organic layer waswashed with water, brine, dried over Na₂SO₄ and concentrated to give acrude product 6-2. Purification was carried out by column chromatographyto yield pure (61.7 g, 91.7%) as pale yellow oil.

Step B: Fluorination

To a stirred solution of diethylamine sulphur trifluoride (32.3 mL,0.2006 mol) in THF (400 mL), was added compound 6-2 during the span of 3h at RT. After completion of addition, stirring was continued forfurther 1 h. The mixture was extracted with ethylacetate and combinedorganic phase was washed with saturated solution of NaHCO₃. Removal ofsolvent under vacuum lead to a crude product, which was purified bycolumn chromatography using hexane grading to 3% EtOAc in hexaneafforded product 6-3 (70.4 g, 69.9%) as pale yellow oil.

Step C: Reduction

To a mechanically stirred solution of LiBH₄ (230.8 mL, 0.4651 mol) inTHF (2.0 L), methyl ester (100.0 g, 0.3322 mol) in THF (1.0 L) was addeddropwise 6-3 through addition funnel during the span of 3 h at −15° C.under N₂. After the completion of addition, stirring was continued for 4h at RT. Saturated solution of NH₄Cl (500 mL) was added dropwise to theabove mixture and extracted with EtOAc. The combined organic phase waswashed with water, brine, dried over Na₂SO₄ and concentrated undervacuum. Residual oil was dissolved in 1N HCl (200 mL), extracted withdiethylether and pH of the aq. layer was adjusted to 10 with the help ofNH₄OH (50%, 300 mL). The resultant was extracted with EtOAc and combinedextracts were concentrated under vacuum to give product 6-4 (86.2 g,95.0%) as pale brown oil.

Step D: Deprotection

A mixture of alcohol 6-4 (50.g, 0.18315 mol) and Pd(OH)₂ on carbon (20%,6.26 g, 0.04395 mol) in absolute ethanol (500 mL) was stirred for 7 hunder the pressure of hydrogen at 50-60 psi. After the reaction,charcoal was removed by filtration and residue was concentrated on rotaevaporator to provide for product 6-5 (15.8 g, 92.7%) as pale brown oil.

Step E: Boc-protection

To a stirred mixture of amino alcohol 6-5 (15.0 g, 0.16129 mol) andK₂CO₃ (33.39 g, 0.24195 mol) in aq. dioxane (about 25%, 375 mL dioxanein 125 mL water), (Boc)₂O (38.66 g, 0.17733 mol) was added drop wise at0° C. The reaction mixture was stirred overnight at RT after theaddition. Saturated solution of KHSO₄ was added to the above mixture toadjust the pH 3-4 and extracted with EtOAc. The organic phase wasconcentrated under vacuum to give pure product 6-6 (27.7 g, 89.0%) as apale brown oil.

Step F: Oxidation to Aldehyde

To a cooled (−78° C.), stirred solution of oxalyl chloride (84 mmol) inCH₂Cl₂ (180 mL) was added a solution of DMSO (168 mmol) in CH₂Cl₂ (90mL). After 1 h, a solution of alcohol 6-6 (56 mmol) in CH₂Cl₂ (90 mL)was added. After 1 h, triethyl amine (281 mmol) was added and stirredfor a further hour. Then a solution of saturated aq. NH₄Cl was added andallowed to warm to RT. The organics were separated, washed with H₂O(×2), saturated brine (×2), then dried, filtered and evaporated underreduced pressure to give the crude aldehyde. Purification by columnchromatography affored the pure (S)-aldehyde 6-7.

Starting from the other enantiomer, (L)-serine methyl ester leads to the(R) enantiomer (6-8).

Example 7-A Preparation for Intermediate with β-Fluoromethyl Side Chain

Step A: Formation of(S)-3-((benzyloxy)carbonyl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid

To a stirred solution of compound 7-1 (10.0 mmol) in 20 mL of DCM wasadded 10 mL of TFA. The mixture was stirred at RT for 24 h. The reactionprogress was followed by LC/MS. After completion, the solvent and TFAwere removed by evaporation under reduced pressure and lyophilization toget white solid as TFA salts. The crude solid was suspended in 50 mL ofTHF and N-carboethoxy phthalimide (10.5 mmol), Et₃N (10 mmol) wereadded. The mixture was refluxed under N₂ for 18 h. The reaction wascooled and the solvents were evaporated. DCM was added and washed withwater, brine, dried over sodium sulfate, filter and concentrated.Purification by chromatography on silica gel column (hexane/EtOAc) togive 2.68 g of colorless oil, compound 7-2.

Step B: Formation of (S)-benzyl4-hydroxy-3-(1,3-dioxoisoindolin-2-yl)butanoate

To a stirred solution of(S)-3-((benzyloxy)carbonyl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid(compound 7-2, 6.07 mmol) in 30 mL of dry THF at −15° C. weresuccessively added N-methylmorpholine (6.07 mmol),iso-butylchloroformate (6.07 mmol). After stirring for 5 min at −15° C.,a solution of NaBH₄ (689 mg, 18.21 mmol) in 2.73 mL of water were addedat once. The reaction was stirred at −15° C. for 2 min, then hydrolyzedwith water (30 mL). Extracted with EtOAc (×3), washed with water (×3),brine (×1), dried over sodium sulfate, filtered, concentrated.Purification by chromatography on silica gel column (hexane/EtOAc) togive 1.9 g of colorless oil, compound 7-3.

Step C: Formation of (S)-benzyl4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanoate

To a stirred solution of (S)-benzyl4-hydroxy-3-(1,3-dioxoisoindolin-2-yl)butanoate (7-3, 5.6 mmol) inacetonitrile (28 mL) were added perfluoro-1-butane sulfonyl fluoride(44.8 mmol), diisopropylethylamine (44.8 mmol), anddiisopropylethylaminie trihydrofluoride (134 mmol). The mixture wasstirred at 50° C. overnight. The reaction progress was followed byLC/MS. After completion, the reaction was cooled to RT and thenevaporated under reduced pressure. The mixture was then partitioned withDCM, washed with water (×3), brine (×2), dried over sodium sulfate,filtered, concentrated. Purification by chromatography on silica gelcolumn (hexane/EtOAc) to give light yellow oil, compound 7-4.

Step D: Formation of (S)-4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanal

To a stirred solution of (S)-benzyl4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanoate (compound 7-4, 0.5 mmol)in dry ether (5 mL) was added dropwise to diisobutylaluminum hydride(1.0 M in toluene, 1.5 mmol) at −78° C. The reaction was stirred at −78°C. for approximately 30 min as monitored by LC/MS. After completion, thereaction was quenched by adding water (10 mL) at −78° C. Extracted withethyl acetate, washed with water (×3), brine (×2), dried over sodiumsulfate, filtered and concentrated. The crude product, compound 7-5, wasused in the next reaction step.

Example 7-B Alternate route for making compound 7-5 Step A: Preparationof Compound 7-6

To prepare (S)-4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanoic acid,compound 7-4 (0.20 mmol) was dissolved in ethanol (5 mL). This solutionwas purged with nitrogen for 10 minutes, then 10% palladium on carbonwas added (0.02 mmol of palladium) under an atmosphere of nitrogen.Hydrogen was then bubbled rapidly through the solution, while stirring,for approximately 1 h. The reaction progress was followed with LC/MS.

The reaction mixture was filtered through celite to remove thepalladium. The celite was rinsed twice with methylene chloride. Thefiltrate was then concentrated to give the crude product, compound 7-6.The crude product was used for the next reaction step.

Step B: Formation of (S)—S-ethyl4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanethioate

Compound 7-5 (0.20 mmol), 1,3 dicyclohexyl carbodiimide (0.30 mmol),ethanethiol (0.6 mmol), and 4-dimethylaminopyridine (0.10 mmol) weredissolved in DMF (5 mL). The mixture was stirred overnight at roomtemperature. The reaction was monitored with LC/MS.

EtOAc was added to the reaction mixture. This was then washed with water(2×) and brine (2×). The EtOAc layer was then dried over sodium sulfate,filtered, and concentrated. The crude product, compound 7-7, was thenpurified using flash chromatography.

Step C: Formation of (S)-4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanal

Compound 7-7 (0.20 mmol) was dissolved in dry acetone (10 mL). 10%Palladium (0.02 mmol) on carbon was then added under an atmosphere ofnitrogen. Triethyl silane (0.5 mmol) was then added. Bubbling occurredafter about 10 seconds, and the reaction was allowed to continue untilthe bubbling ceased (30 min). The reaction was monitored using LC/MS.

The reaction mixture was filtered through a celite plug. The plug waswashed twice with methylene chloride, and the filtrate was thenconcentrated to give the crude product, compound 7-5. The crude productwas used in the next reaction.

Starting from the other (R) enantiomer,(R)-3-((benzyloxy)carbonyl)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid,leads to the (R) enantiomer (7-8), having the following chemicalstructure:

Example 7-C Alternate Preparation for Intermediate with β-FluoromethylAldehyde Side Chain

Step A: Preparation of Compound 7-10

Methanol (300 mL) was charged to a 1000 mL round bottom flask and thesystem was cooled with an ice bath. Acetyl chloride (89.3 mL; 1251 mmol)was added dropwise over a period of 15 minutes. The resulting solutionwas warmed to ambient temperature and the (S)-2-amino-4-pentenoic acid(7-9) (6.0 g; 139 mmol) was added in a single portion. The reactionmixture was heated at reflux for two hours and was then cooled toambient temperature. The mixture was then concentrated in vacuo toprovide a pale yellow oil. The product was dispersed in ethyl acetate(150 mL) and was again concentrated in vacuo. This sequence was repeatedfour times. The product 7-10 was an oil that solidified upon standingunder vacuum overnight. ¹H NMR analysis showed the product to be ofsufficient purity for use without further purification.

TLC: R_(f)=7.1 (silica; eluant 5:3:1 CHCl₃:MeOH:(7:3 H₂O: AcOH);visualization with ninhydrin).

¹H NMR (400 MHz, CD₃OD): δ 5.84-5.73 (m, 1H), 5.32-5.26 (m, 2H), 4.17(dd, 1H, J=7.0, 1.6 MHz), 3.84 (s, 3H), 2.73-2.65 (m, 2H); (400 MHz,d6-DMSO): δ 8.7 (br s, 3H), 5.81-5.73 (m, 1H), 5.21-5.14 (m, 2H), 4.11(t, 1H, J=6.1 Hz), 3.72 (s, 3H), 2.60 (dd, 2H, J=7.1, 0.9 Hz).

¹³C NMR (101 MHz, d6-DMSO): δ 169.33, 131.37, 119.88, 52.65, 51.65,34.22.

Step B: Preparation of Compound 7-11

The crude (S)-methyl-2-amino-4-pentenoate hydrochloride (7-10) from theprevious step was dissolved in THF (190 mL) with gentle warming. Theresulting solution was added dropwise to a solution of LiAlH₄ in THF(280 mL of a 1.0 M solution) at a rate such that the internaltemperature remained at approximately 5° C. Periodically, slight heatingwas used to warm the addition funnel containing the(S)-methyl-2-amino-4-pentenoate hydrochloride solution to redissolvecrystallized amino ester. Upon completion of addition, the additionfunnel was rinsed with an additional 20 mL portion of THF. The mixturewas then diluted with diethyl ether (500 mL) and the excess LiAlH₄ wasdestroyed by the sequential addition of H₂O (11 mL), 15% (w/v) aqueousNaOH (11 mL) and H₂O (33 mL) added at a rate such that the internaltemperature remained below 10° C. The mixture was filtered and thefilter cake was washed with additional diethyl ether. The filtrate wasdried over Na₂SO₄, filtered, and concentrated in vacuo to provide ayellow liquid (7-11; 13.4 g; 95% mass recovery based upon 139.0 mmol of(S)-2-amino-4-pentenoic acid). The amino alcohol (7-11) may be purifiedby distillation (110° C.; 20 torr). However, minimal improvement wasobserved in the subsequent step so the crude material was generally usedwithout further purification.

¹H NMR (400 MHz, d6-DMSO): δ 5.87-5.77 (m, 1H), 5.05-4.97 (m, 2H), 3.26(dd, 1H, J=10.3, 5.1 Hz), 3.14 (dd, 1H, J=10.3, 6.7 Hz), 2.69-2.63 (m,1H), 2.15-2.09 (m, 1H), 1.92-1.86 (m, 1H).

¹³C NMR (101 MHz, d6-DMSO): δ 136.49, 116.31, 66.13, 52.53, 38.51.

Step C: Preparation of Compound 7-12

(S)-2-Amino-4-pentenol (7-11; 13.4 g; 132.5 mmol) and Na₂CO₃ (70.8 g;668.0 mmol) were dissolved in H₂O (400 mL). CH₃CN (700 mL) andmethyl-2-[(succinimidooxy)carbonyl]benzoate (33.1 g; 119.4 mmol) wereadded and the resulting mixture was vigorously stirred at ambienttemperature. After 2 hours, TLC analysis showed the consumption ofmethyl-2-[(succimimidooxy)carbonyl]benzoate. The majority of the CH₃CNwas removed on a rotary evaporator and the remaining material wastransferred to a separatory funnel and extracted with EtOAc (3×100 mL).The combined EtOAc extracts were washed with 0.5 M HCl (2×250 mL) andbrine (250 mL). The EtOAc phase was dried over Na₂SO₄, filtered andconcentrated in vacuo to provide a yellow oil (7-12; 19.3 g; 70%) thatwas used in the next step without further purification.

¹H NMR (400 MHz, d6-DMSO): δ 7.90-7.83 (m, 4H), 5.74-5.64 (m, 1H),4.99-4.91 (m, 3H), 4.27-4.20 (m, 1H), 3.90-3.84 (m, 1H), 3.63-3.58 (m,1H), 2.64-2.44 (m, 2H).

¹³C NMR (101 MHz, d6-DMSO): δ 168.25, 134.86, 134.42, 131.37, 122.94,117.41, 60.63, 53.47, 32.59.

Step D: Preparation of Compound 7-13

N,N-Diisopropylethylamine (215 mL; 1240 mmol), triethylaminetrihydrofluoride (81 mL; 496 mmol) and perfluoro-1-butanesulfonylfluoride (15.0 mL; 83.5 mmol) were added to a solution of 7-12 (19.1 g;82.7 mmol) in PhCF₃ (310 mL) and the resulting mixture was stirred atambient temperature. Additional perfluoro-1-butanesulfonyl fluoride (7.5mL; 41.8 mmol) was added after each of 60, 90, 120, 150, and 180minutes. After a total of 18 hours, the reaction mixture was transferredto a separatory funnel and was washed twice with 1.0 N HCl, twice withsaturated aqueous NaHCO₃ and once with H₂O. The organic phase was driedover Na₂SO₄, filtered, and concentrated to provide an orange oil. Thecrude material was loaded onto a pad of silica and eluted with 4:1hexane:EtOAc to provide the product (7-13) as a yellow oil (15.4 g;80%).

¹H NMR (400 MHz, d6-DMSO): δ 7.88-7.81 (m, 4H), 5.77-5.66 (m, 1H),5.04-4.88 (m, 2.5H), 4.80-4.73 (m, 1H), 4.65-4.61 (m, 0.5H), 4.60-4.49(m, 1H), 2.68-2.47 (m, 2H).

¹³C NMR (101 MHz, d6-DMSO): δ 167.87, 134.79, 133.77, 130.94, 123.26,118.21, 81.82 (d, J=170 Hz), 50.47 (d, J=19 Hz), 31.40 (d, J=6 Hz).

Step E: Preparation of Compound 7-8

Compound 7-13 (15.3 mmol) was dissolved in 2:1 CH₃OH:H₂O (1500 mL) and asolution of OsO₄ in H₂O (29.3 mL of a 4% w/v solution) was added. NaIO₄(42.2 g; 197.2 mmol) was then added in a single portion and theresulting mixture was stirred at ambient temperature. After 3 hours, themixture was filtered to remove precipitated solids and the filter cakewas washed with EtOAc. The filtrate was concentrated in vacuo to removethe majority of the organic solvents. The residue was extracted withthree portions of EtOAc and the combined EtOAc extracts were dried overNa₂SO₄, filtered, and concentrated. The residue was dissolved in CH₂Cl₂,loaded onto a pad of silica gel and sequentially eluted with 20%, 30%,40%, 50%, and 100% EtOAc in hexane. Compound 7-8 was present in the30%-50% fractions but contaminated with a more-polar impurity. Thefractions were combined and concentrated and the residue was applied toa second pad of silica and eluted with 30% EtOAc in hexane to provideCompound 7-8 as a light yellow solid (11.1 g; 72%)

¹H NMR (400 MHz, d6-DMSO): δ 9.61 (s, 1H), 7.91-7.83 (m, 4H), 4.97-4.94(m, 1H), 4.78 (t, 0.5H, J=9.3 Hz), 4.69-4.64 (m, 1H), 4.57-4.53 (m,0.5H), 3.28-3.02 (m, 2H).

¹³C NMR (101 MHz, d6-DMSO): δ 200.14, 167.65, 134.73, 131.15, 123.24,81.80 (d, J=171 Hz), 44.81 (d, J=21 Hz), 40.64 (d, J=6 Hz).

Example 7-C Alternate Synthesis of Compound 7-12

Step A: Preparation of Compound 7-14

Compound 7-9 was refluxed with 2.2 equivalents of phthalic anhydride inthe presence of 2.2 equivalents triethylamine in ethyl acetate until thereaction was complete. The solvent was removed under pressure. Theresidual was dissolved in water with a pH of 4 and then extracted withethyl acetate. The combined organic layers were washed twice with waterhaving a pH of 4. Then, the organic phase was dried with sodium sulfate.The solvent was removed providing 7-14 as a white solid.

Step B: Preparation of Compound 7-12

Compound 7-14 and 1.2 equivalents of DIEA and 1.1 equivalent of BOP inTHF was stirred at room temperature until a clear solution formed. Thesolution was cooled to 0° C., and then 1.0 equivalent of NaBH₄ wasadded. The reaction mixture was stirred at 0° C. under N₂ until reactioncompletion. The solvent to changed to DCM and the reaction was washedonce with water. The DCM phase was loaded onto a silica gel plug, andflushed with 15% EtOAc in hexanes to give Compound 7-12 as a colorlessoil.

Example 8 Synthesis of Intermediate (S)-tert-butyl4-oxobutan-2-ylcarbamate

Azeotropic mixture of (S)-ethyl 3-(tert-butoxycarbonylamino) butanoate8-1 (1 eq.) and toluene (x=3) was dissolved in dichloromethane andcooled to −78° C. Then 1M solution of DIBAL in toluene (2 eq.) was addeddropwise under N₂ atmosphere and stirred at −78° C. for 2 h.

The reaction was quenched with methanol and concentrated. To theconcentrated residue was added 2 M potassium sodium tartrate solution at0° C. and stirred vigorously at room temperature for 30 min. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over sodium sulfate filtered,evaporated and dried under reduced pressure to provide compound 8-2 as alight yellow viscous liquid.

MS: MH+=188.2

Example 9 Synthesis of (R)-tert-butyl 4-oxobutan-2-ylcarbamate Step A:Synthesis of (R)-((benzyl) 3-(tert-butoxycarbonylamino) butanoate

To (R)-benzyl 3-aminobutyrate sulfate salt 9-1 (1 eq.) in THF was addedBoc-anhydride (2 eq.) and diisopropylethylamine (4 eq.). The reactionmixture was stirred at room temperature for 72 h. The reaction mixturewas concentrated and partitioned between ethyl acetate and water. Theorganic layer was separated, washed with water and brine, dried oversodium sulfate, filtered, evaporated and dried under reduced pressure toprovide compound 9-2 as a white solid.

MS: MH+=294.0

Step B: Synthesis of (R)-tert-butyl 4-oxobutan-2-ylcarbamate

Azeotropic mixture of (R)-((benzyl) 3-(tert-butoxycarbonylamino)butanoate 9-2 (1 eq.) and toluene (x=3) was dissolved in dichloromethaneand cooled to −78° C. A 1 M solution of DIBAL in toluene (2 eq.) wasadded dropwise under N₂ atmosphere and stirred at −78° C. for 2 h. Thereaction was quenched with methanol and then concentrated. To theconcentrated residue was added 2 M potassium sodium tartrate solution at0° C. and stirred vigorously at room temperature for 30 min. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over sodium sulfate,filtered, evaporated and dried under reduced pressure to providecompound 9-3 as a colorless viscous liquid.

MS: MH+=188.2

Example 10 Synthesis of tert-butyl 2-methyl-4-oxobutan-2-ylcarbamateStep A: Synthesis of methyl 3-amino-3-methylbutanoate

To 3-amino-3-methyl-butyric acid 10-1 (1 eq.) in methanol at 0° C. wasadded 2 eq. of thionyl chloride. The reaction mixture was warmed to roomtemperature and stirred overnight. The solvent was evaporated to giveazeotropic mixture of 10-2 and toluene (x=3) which was used for Step B.

MS: MH+=132.1

Step B: Synthesis of methyl3-tert-butoxycarbonylamino)-3-methylbutanoate

To methyl 3-amino-3-methylbutanoate HCl salt 10-2 (1 eq.) in THF wasadded Boc-anhydride (2 eq.) and diisopropylethylamine (4 eq.). Thereaction mixture was stirred at room temperature for 48 h. The reactionmixture was concentrated and partitioned between ethyl acetate andwater. The organic layer was separated, washed with water and brine,dried over sodium sulfate, filtered, evaporated and dried under reducedpressure to provide product 10-3 as a white solid.

MS: MH+=232.1

Step C: Synthesis of tert-butyl 2-methyl-4-oxobutan-2-ylcarbamate

Azeotropic mixture of methyl3-tert-butoxycarbonylamino)-3-methylbutanoate 10-3 (1 eq.) and toluene(x=3) was dissolved in dichloromethane and cooled to −78° C. To this wasadded dropwise 1 M solution of DIBAL in toluene (2 eq.) under N₂atmosphere and stirred at −78° C. for 2 h. The reaction was quenchedwith methanol and concentrated. To concentrated residue was added 2 Mpotassium sodium tartrate solution at 0° C. and stirred vigorously atroom temperature for 30 min. The mixture was partitioned between ethylacetate and water. The organic layer was washed with brine, dried oversodium sulfate, filtered, evaporated and dried under reduced pressure toprovide product 10-4 as a colorless viscous liquid.

MS: MH+=202.1

Example 11 Synthesis of Phenylimidazole Free Amine Intermediate

Step A: Preparation of Compound 11-3

To a 5-necked flask containing 1 eq. of Compound 11-1 was added 0.7 eq.of K₂CO₃ to give a 0.25M solution of K₂CO₃ in acetone. After beingstirred under N₂ for 45 minutes, 1.0 eq. of Compound 11-2 in 1 M ofacetone was added followed by addition of 0.2 eq. of KI in 5 M acetone.When the reaction is completed (about 3 hours), the reaction mixture wascooled with an ice bath. Ice water (equal to approximately 2.5× volumeof acetone used in reaction) was added via addition funnel at such aspeed that the temperature did not exceed 15° C. After being stirred inan ice bath for one hour, the product was collected by vacuumfiltration. The filter cake was washed 3 times with 20% acetone and 3times with water. The filter cake was air-dried and further dried in anoven at 50° C./5 torr until a consistent weight is reached. Yield 96%.HPLC purity: 99%.

Step B: Preparation of Compound 11-4

To a 0.19 M toluene solution of 11-3 in a reaction flask was added 20eq. of NH₄OAc. The mixture was stirred under reflux until the reactionwas completed (about 8 h). It was cooled to RT and then water (equal toapproximately one fourth of the volume of toluene used in the reaction)was added. The organic phase was separated and washed with water, sat.NaHCO₃, and dried over MgSO₄. The solvent was removed in vacuo to give11-4. Yield 99.6%. HPLC purity: 91.4%.

Step C: Preparation of Compound 11-5

A flask containing a 0.5 M DMF and K₂CO₃ solution of 11-4 was stirredunder N₂ for 30 min at 0-5° C., and then 1.1 eq. of PhCH₂Br was added toit. The mixture was then stirred at RT overnight. It was then stirred inan ice bath during which ice water (approximately equal to the volume ofDMF used in the reaction) was added dropwise. The product was collectedby vacuum filtration, washed twice with 50% DMF, twice with 25% DMF andthree times with water. The solid was dried in an oven at 50° C./5 torr.Yield 95%. HPLC purity: 94%.

Step D: Preparation of Compound 11-6

MeOH was added to a flask and placed in an ice bath. To this was added9.85 eq. of CH₃COCl dropwise over 30 min. followed by 1 eq. of 11-5 toform a 0.25M solution of 11-5 in MeOH. The mixture was stirred at RTuntil the reaction was completed (about 12 h). After removing thesolvent under reduced pressure, the obtained solid was suspended in MeOH(equal to approximately one half of the volume of MeOH used in thereaction) and stirred at 0-5° C. To this mixture were added 2.5 MNaOH/MeOH solution dropwise until the pH reached about 10 and water wasthen added. After being stirred at 0-5° C. for 1 h, the product wascollected by filtration. It was dried in an oven at 50° C./5 torr. Yield90.5%. HPLC purity: 97.0%. Optical purity was determined to be >99%(enantiomeric excess (ee)).

Example 12 Preparation of β-Methoxymethyl Side Chain Intermediate

Step A: Preparation of Compound 12-2

To a 500 mL round bottom flask was added Compound 12-1 (7.95 g; 25.7mmol), 16.0 g of 2,6-di-tert-butyl-4-methylpyridine (16.0 g; 77.9 mmol)and 100 mL anhydrous DCM. Subsequently, 11.36 g ofmethyl-trifluoromethane sulfonate was added. The reaction mixture wasstirred at room temperature under N₂ and monitored by HPLC. HPLCmonitoring showed at t=17 h that there was 76.0% Compound 12-2, 9.9%Compound 12-1, 14.1% byproduct; at t=20 h, there was 76.4% Compound12-2, 16.2% byproduct, 7.4% Compound 12-1. The reaction was stopped byfiltering out the solids. The solids were washed with CH₂Cl₂. Thecombined filtrate was washed with 0.5 N HCl (2×100 mL) and dried withNa₂SO₄ and concentrated. Flash column chromatography (200 g silica gel,20% EtOAc in hexanes) gave 5.28 g of tan oil as 12-2. HPLC purity=93.9%and used for the next step.

Step B: Preparation of Compound 12-3

A solution of Compound 12-2 (1.10 g, 3.6 mmol) in anhydrous DCM (22 mL)was cooled to −78° C. DIBAL (7.12 mL of 1.0M solution in CH₂Cl₂) wasadded. The reaction mixture was stirred at −120° C.±3° C. (externaltemperature) and monitored by HPLC. An in process control (IPC) samplewas instantly quenched in pre-chilled MeOH at −120° C. and then preparedfor HPLC for t=0 reading. The internal temperature was maintained at−118° C.±3° C. All IPC samples (t=0, t=1 h, t=2 h) indicated the absenceof Compound 12-2 in the reaction mixture. The reaction was deemedcomplete at t=3 h and quenched with methanol. A temperature of −120°C.±2° C. was maintained during the entire quenching process. HPLCindicated reaction mixture contained an aldehyde:alcohol ratio of95.1:4.9. The reaction mixture was concentrated to dryness thenredissolved in CH₂Cl₂, washed in Na₂CO₃ (2×50 mL) and brine (2×50 mL),dried with Na₂SO₄ and concentrated to a pale yellow oil. HPLC indicated82% pure for Compound 12-3.

The compounds in the table below were prepared using the methodologydescribed in the previous Examples and Methods. The following tablesalso include compounds described in the experimentals. The startingmaterials used in the synthesis are recognizable to one of skill in theart and are commercially available or may be prepared using knownmethods.

The compounds in Table 1 were named using ACD/Name Batch Version 5.04(Advanced Chemistry Development Inc.; Toronto, Ontario;www.acdlabs.com). The compounds in Table 2 and Table 3 were named usingAutoNom 2000 (Automatic Nomenclature) for ISIS/Base, implementing IUPACstandardized nomenclature. In one embodiment, provided is a stereoisomerof any one of the compounds in Tables 1, 2, or 3. In one aspect, thestereoisomer is an enantiomer. In another aspect, the stereoisomer is adiastereomer.

TABLE 1 Compound Structure MH+ Name 1

511.2 N-(3-aminopropyl)-N-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}morpholine-4- carboxamide 2

508.2 N-(3-aminopropyl)-N-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}piperidine-1- carboxamide 3

488.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]piperidine-1-carboxaimide 4

448.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′,N′-dimethylurea 5

478.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-(2-methoxyethyl)urea 6

532.3 methyl (2S)-1-({(3-aminopropyl)[(1R)-1-1-(1-benzyl-4-phenyl-1H-imidazol-2- yl)-2,2-dimethylpropyl]amino}carbonyl)pyrroli- dine-2-carboxylate 7

707.7 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-hydroxyurea 8

474.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]pyrrolidine-1-carboxamide 9

503.2 (2R)-2-(aminomethyl)-N-(3- aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl 1H-imidazol-2-yl)-2,2- dimethylpropyl]pyrrolidine-1- carboxamide10

490.2 (3S)-N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine- 1-carboxamide 11

490.2 (3R)-N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine- 1-carboxamide 12

434.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-methylurea 13

489.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]piperazine-1-carboxamide 14

571.4 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′-bipiperidine-1- carboxamide 15

502.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-thien-2-ylurea16

502.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-thien-3-ylurea17

515.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-(3,5-dimethylisoxazol-4-yl)urea 18

565.2 567.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethyipropyl]-N′-(2,6-dichloropyridin-4-yl)urea 19

500.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-furylmethyl)urea 20

521.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethyipropyl]-N′-(4-cyanophenyl)urea 21

532.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethyipropyl]-N′-(3,4-difluorophenyl)urea 22

586.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]-N′-(3,5-dinitrophenyl)urea 23

496.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethyipropyl]-N′-phenylurea 24

520.3 (3R)-N-[(3S)-3-amino-4-hydroxybutyl]-N-](1R)-1-(1-benzyl-4-phenyl-1H- imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide 25

507.3 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]piperazine-1- carboxamide 26

507.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]piperazine-1- carboxamide 27

504.3 (3R)-N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1- carboxamide 28

504.3 (3S)-N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1- carboxamide 29

478.3 N-[(3S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]- N′,N′-dimethylurea 30

514.3 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1Himidazol-2-yl)-2,2-dimethylpropyl]-N′- phenylurea 31

466.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]- N′,N′-dimethylurea 32

514.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- phenylurea 33

496.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (2-methoxyethyl)urea 34

549.3 4-acetyl-N-[(2R)-3-amino-2- fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]piperazine-1- carboxamide35

510.2 (4R)-N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H- imidazol-2-yl)-2,2-dimethylpropyl]-4-hydroxyisoxazolidine-2-carboxamide 36

522.2 (3R)-N-(3-amino-2-fluoropropyl)-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3- hydroxypiperidine-1-carboxamide 37

508.2 N-[(3S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N- (2-methoxyethyl)urea 38

508.2 (3R)-N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H- imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide 39

508.2 (3S)-N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H- imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide 40

522.3 (3S)-N-[(2R)-3-amino-2-fluoropropyl]- N-[(1R)-1 -(1-benzyl-4-phenyl-1H- imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1-carboxamide 41

579.3 ethyl 4-({[(2S)-3-amino-2- fluoropropyl][(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]amino}carbonyl)piperazine-1-carboxylate 42

579.3 ethyl 4-({[(2R)-3-amino-2- fluoropropyl][(1 R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2- dimethylpropyl]amino}carbonyl)piperazine-1-carboxylate 43

599.3 N-[2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(ethylsulfonyl)piperazine-1-carboxamide 44

522.3 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- hydroxypiperidine-1-carboxamide 45

522.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- hydroxypiperidine-1-carboxamide 46

589.4 N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′-bipiperidine-1′- carboxamide 47

589.4 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′- bipiperidine-1′-carboxamide 48

521.3 N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)- 2,2-dimethylpropyl]-4-methylpiperazine-1-carboxamide 49

521.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- methylpiperazine-1-carboxamide 50

508.3 N-[(3 S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′ (2-hydroxyethyl)-N′-methylurea 51

496.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (2-hydroxyethyl)-N′-methylurea 52

403.2 1-[(1R)-1-(1-benzyl-4-phenyl-1H- imidazol-2-yl)-2,2-dimethylpropyl]tetrahydropyrimidin- 2(1H)-one 53

496.3 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (2-hydroxyethyl)-N′-methylurea 54

550.2 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (3,4-difluorophenyl)urea 55

520.2 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- thien-3-ylurea 56

520.2 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- thien-3-ylurea 57

591.4 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- morpholin-4-ylpiperidine-1-carboxamide 58

591.7 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- morpholin-4-ylpiperidine-1-carboxamide 59

508.3 N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)- 2,2-dimethylpropyl]morpholine-4-carboxamide 60

585.3 N-(3-amino-2-fluoropropyl)-N-[( 1 R)- 1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)- 2,2-dimethylpropyl]-4-(methylsulfonyl)piperazine-1- carboxamide 61

585.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (methylsulfonyl)piperazine-1-carboxamide 62

588.4 N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)- 2,2-dimethylpropyl]-4-cyclohexylpiperazine-1-carboxamide 63

539.2 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (4-cyanophenyl)urea 64

539.2 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (4-cyanophenyl)urea 65

613.3 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (propylsulfonyl)piperazine-1-carboxamide 66

613.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (propylsulfonyl)piperazine-1-carboxamide 67

613.3 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (isopropylsulfonyl)piperazine-1-carboxamide 68

613.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (isopropylsulfonyl)piperazine-1-carboxamide 69

611.2 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (cyclopropylsulfonyl)piperazine-1-carboxamide 70

611.2 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (cyclopropylsulfonyl)piperazine-1-carboxamide 71

627.2 N-[(2S)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (butylsulfonyl)piperazine-1-carboxamide 72

627.2 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (butylsulfonyl)piperazine-1-carboxamide 73

601.4 N-[(3S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′- bipiperidine-1′-carboxamide 74

551.3 N-[(3S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (4-cyanophenyl)urea 75

562.3 N-[(3S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- (3,4-difluorophenyl)urea 76

615.3 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S)-3-fluoropyrrolidin-3-yl]methyl}- 1,4′-bipiperidine-1′-carboxamide 77

615.3 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N- {[(3R)-3-fluoropyrrolidin-3-yl]methyl}- 1,4′-bipiperidine-1′-carboxamide 78

628.3 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(2S,3S)-2-(hydroxymethyl)pyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′- carboxamide 79

522.3 N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-tetrahydro-2H- pyran-4-ylurea 80

522.3 N-[(2R)-3-amino-2-fluoropropyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′- tetrahydro-2H-pyran-4-ylurea 81

549.3 N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)- 2,2-dimethylpropyl]-4-(dimethylamino)pipendine-1- carboxamide 82

549.3 N-[(2R)-3-amino-2-fluoropropyl]-N- ](1R)-1-(1-benzyl-4-phenyl-1H-(dimethylamino)piperidine-1- carboxamide 83

613.4 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N- {[(3R,4R)-4-hydroxypyrrohdin-3-yl]methyl}-1,4′-bipiperidine-1′- carboxamide 84

613.3 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N- {[(3S,4S)-4-hydroxypyrrolidin-3-yl]methyl }-1,4′-bipiperidine-1′- carboxamide 85

611.2 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-[(3-fluoropyrrolidin-3-yl)methyl]-4- (methylsulfonyl)piperazine-1-carboxamide 86

611.2 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S)-3-fluoropyrrolidin-3-yl]methyl}- -(methylsulfonyl)piperazine-1-carboxamide 87

611.2 N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3R)-3-fluoropyrrolidin-3-yl]methyl}- 4-(methylsulfonyl)piperazine-1-carboxamide 88

597.2 N-[(3R)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (methylsulfonyl)piperazine-1-carboxamide 89

597.2 N-[(3S)-3-amino-4-hydroxybutyl]-N- [(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4- (methylsulfonyl)piperazine-1-carboxamide

TABLE 2 Compound Structure MH+ Name 90

498.2 1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H- imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea 91

498.2 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H- imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea 92

588.2 1,1-Dioxo-1-thiomorpholine-4- carboxylic acid((R)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 93

540.2 Morpholine-4-carboxylic acid ((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]- 2,2-dimethyl-propyl}-amide 94

540.2 Morpholine-4-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]- 2,2-dimethyl-propyl}-amide 95

616.3 4-Methanesulfonyl-piperidine-1- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 96

502.6 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea 97

502.6 1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea 98

588.2 1,1-Dioxo-1-thiomorpholine-4- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 99

616.3 4-Methanesulfonyl-piperidine-1- carboxylic acid((R)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 100

488.6 1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea 101

480.6 1-(3-Amino-3-methyl-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H- imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea 102

494.6 1-(3-Amino-3-methyl-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H- imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea 103

488.6 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea 104

571.7 4-Methyl-piperazine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)- 1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide 105

571.7 4-Methyl-piperazine-1-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)- 1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide 106

466.6 1-(3-Amino-3-methyl-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H- imidazol-2-yl]-2,2-dimethyl-propyl}-urea 107

558.3 Morpholine-4-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 108

558.3 Morpholine-4-carboxylic acid ((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 109

516.2 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea 110

516.2 1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea 111

542.3 Pyrrolidine-1-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 112

542.3 Pyrrolidine-1-carboxylic acid ((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 113

544.3 Morpholine-4-carboxylic acid ((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 114

528.3 Pyrrolidine-1-carboxylic acid ((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 115

514.3 1-((S)-3-Amino-4-methoxy-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea 116

554.3 Pyrrolidine-1-carboxylic acid ((S)-3-amino-4-methoxy-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 117

570.3 Morpholine-4-carboxylic acid ((S)-3-amino-4-methoxy-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 118

592.3 1,1-Dioxo-1-thiomorpholine-4- carboxylic acid((S)-3-amino-2-fluoro- propyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]- 2,2-dimethyl-propyl}-amide 119

474.2 1-((S)-3-Amino-2-fluoro-propyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea 120

470.6 1-(3-Amino-propyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea 121

484.6 1-(3-Amino-propyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl- urea 122

551.7 1-(3-Amino-propyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-3-(3,5-dimethyl-isoxazol-4-yl)-urea 123

510.3 Pyrrolidine-1-carboxylic acid (3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5- difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide 124

512.1 Isoxazolidine-2-carboxylic acid (3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 125

603.3 4-Methanesulfonyl-piperazine-1- carboxylic acid(3-amino-propyl)-{(R)- 1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 126

602.3 4-Methanesulfonyl-piperidine-1- carboxylic acid(3-amino-propyl)-{(R)- 1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 127

526.3 Morpholine-4-carboxylic acid (3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5- difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide 128

570.3 Morpholine-4-carboxylic acid ((S)-3-amino-4-methoxy-butyl)-{(R)-1-[1- benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yll-2,2-dimethyl-propyl}- amide 129

502.2 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3- methyl-urea 130

558.3 Morpholine-4-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide131

574.2 1,1-Dioxo-1-thiomorpholine-4- carboxylic acid(3-amino-propyl)-{(R)- 1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 132

542.3 Pyrrolidine-1-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide133

516.2 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- 3,3-dimethyl-urea 134

635.2 4-Methanesulfonyl-piperazine-1- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 135

583.3 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-(3,5-di-methyl-isoxazol-4-yl)-urea 136

592.3 1,1-Dioxo-1-thiomorpholine-4- carboxylic acid((S)-3-amino-2-fluoro- propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 137

544.3 Isoxazolidine-2-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide138

542.2 Thiomorpholine-4-carboxylic acid (3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 139

530.3 Isoxazolidine-2-carboxylic acid ((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1- benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 140

528.3 Pyrrolidine-1-carboxylic acid ((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1- benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 141

544.3 Morpholine-4-carboxylic acid ((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1- benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 142

606.3 1,1-Dioxo-1-thiomorpholine-4- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 143

558.2 1-Oxo-1-thiomorpholine-4-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide144

540.1 Morpholine-4-carboxylic acid ((S)-3-amino-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 145

621.3 4-Methanesulfonyl-piperazine-1- carboxylic acid((S)-3-amino-2-fluoro- propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 146

576.1 Morpholine-4-carboxylic acid ((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,3,5-trifluoro-phenyl)-1H-imidazol- 2-yl]-2,2-dimethyl-propyl}-amide147

576.1 Morpholine-4-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,3,5-trifluoro-phenyl)-1H-imidazol- 2-yl]-2,2-dimethyl-propyl}-amide148

540.1 Morpholine-4-carboxylic acid ((R)-3-amino-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 149

586.3 (2R,6S)-2,6-Dimethyl-morpholine-4- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 150

599.7 4-Isopropyl-piperazine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 151

530.6 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3- isopropyl-urea

TABLE 3 Compound Structure MH+ Name 152

542.7 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3- cyclopropylmethyl-urea 153

572.1 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3- (tetrahydro-pyran-4-yl)-urea 154

558.2 Morpholine-4-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(S)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide155

643.8 4-(3-((S)-3-Amino-4-fluoro-butyl)-3-{(R)-1-[1-benzyl-4-(2,5-difluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-ureido)-piperidine-1- carboxylic acid ethyl ester 156

586.3 (2S,6R)-2,6-Dimethyl-morpholine-4- carboxylic acid((R)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 157

558.2 (S)-3-Hydroxy-pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 158

558.2 (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- amide 159

528.2 1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3- cyclopropyl-urea 160

600.7 (S)-2-Hydrazinocarbonyl-pyrrolidine-1- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 161

600.7 (S)-1-((3-Amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}- carbamoyl)-pyrrolidine-2-carboxylicacid methyl ester 162

502.2 1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl }-3- methyl-urea 163

514.2 1-((S)-3-Amino-4-methoxy-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea 164

592.2 Morpholine-4-carboxylic acid ((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3- hydroxy-benzyl)-4-(2,3,5-trifluoro-phenyl)-1H-imidazol-2-yl]-2,2- dimethyl-propyl}-amide 165

620.2 (2S,6R)-2,6-Dimethyl-morpholine-4- carboxylic acid((S)-3-amino-4-fluoro- butyl)-{(R)-1-[1-(3-hydroxy-benzyl)-4-(2,3,5-trifluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide166

542.2 Pyrrolidine-1-carboxylic acid ((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2- yl]-2,2-dimethyl-propyl}-amide167

504.2 N-[(3S)-3-amino-4-fluorobutyl]-N- {(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl]-2,2- dimethylpropyl}-N′-hydroxyurea168

504.2 N-[(3R)-3-amino-4-fluorobutyl]-N- {(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl]-2,2- dimethylpropyl}-N′-hydroxyurea169

632 1-{(R)-1-[1-Benzyl-4-(2,5-difluoro- phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-1-[(S)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-fluoro- butyl]-3-methyl-urea 170

663 ′N-[(S)-3-(1-{(R)-1-[1-Benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-ureido)-1- fluoromethyl-propyl]-N′-methyl-phthalamide

Example 13 Assay for Determining KSP Activity

This example provides a representative in vitro assay for determiningKSP activity in vitro. Purified microtubules obtained from bovine brainwere purchased from Cytoskeleton Inc. (Denver, Colo., USA). The motordomain of human KSP (Eg 5, KNSL1) was cloned, expressed, and purified togreater than 95% homogeneity. Biomol Green was purchased from AffinityResearch Products Ltd. (Matford Court, Exeter, Devon, United Kingdom).Microtubules and KSP motor protein (i.e., the KSP motor domain) werediluted in assay buffer (20 mM Tris-HCl (pH 7.5), 1 mM MgCl₂, 10 mM DTTand 0.25 mg/mL BSA) to a final concentration of 35 μg/mL microtubulesand 45 nM KSP. The microtubule/KSP mixture was then pre-incubated at 37°C. for 10 min to promote the binding of KSP to microtubules.

To each well of the testing plate (384-well plate) containing 1.25 μL ofinhibitor or test compound in DMSO (or DMSO only in the case ofcontrols) were added 25 μL of ATP solution (ATP diluted to aconcentration of 300 μM in assay buffer) and 25 μL of theabove-described microtubule/KSP solution. The plates were incubated atRT for 1 hour. Following incubation, 65 μL of Biomol Green (a malachitegreen-based dye that detects the release of inorganic phosphate) wasadded to each well. The plates were incubated for an additional 5-10minutes then the absorbance at 630 nm was determined using a Victor IIplate reader. The amount of absorbance at 630 nm corresponded to theamount of KSP activity in the samples. The IC₅₀ of each inhibitor ortest compound was then determined based on the decrease in absorbance at630 nm at each concentration, via nonlinear regression using eitherXLFit for Excel or Prism data analysis software by GraphPad SoftwareInc.

Preferred compounds of the invention have a biological activity asmeasured by an IC₅₀ of less than about 1 mM in assay protocols describedin Example 13, with preferred embodiments having biological activity ofless than about 25 μM, with particularly preferred embodiments havingbiological activity of less than about 1000 nM, and with the mostpreferred embodiments having biological activity of less than about 100nM.

Example 14 Inhibition of Cellular Proliferation in Tumor Cell LinesTreated with KSP Inhibitors

Cells are plated in 96-well plates at densities of about 500 cells perwell of a 96-well plate and are allowed to grow for 24 hours. The cellsare then treated with various concentrations of compounds for 72 hours.Then, 100 μl of CellTiter Glo is added. CellTiter Glo is atetrazolium-based assay using the reagent 3-(4,5-dimethylthiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) (U.S.Pat. No. 5,185,450) (see Promega product catalog #G3580, CeIITiter 96Aqueous One Solution Cell Proliferation Assay). The cells are thenincubated in the dark for 30 minutes. The amount of luminescence isdetermined for each well using a Walloc Trilux plate reader, whichcorrelates with the number of cells per well. The number of viable cellsin the wells that receive only DMSO (0.5%) serve as an indication of 0%inhibition, while wells without cells serve as 100% inhibition of cellgrowth.

The compound concentration that results in a 50% growth inhibition(GI₅₀) is determined graphically from sigmoidal dose-response curves oflog-transformed dose values versus cell counts (percent of control) at72 hours of continuous compound exposure.

The cell lines used are listed below.

The cell proliferation assay is performed as described above.

Cancer Cell Lines

Colo 205—colon carcinoma

-   -   RPMI 1640+10% FBS+1% L-glutamine+1% P/S+1% NaPyr.+Hepes    -   +4.5 g/L Glucose +1% NaBicarb.

MDA 435—breast cancer—high met

-   -   EMEM+10% FBS+1% P/S+1% L-Glutamine+1% NEAA 1% NaPyr+1% vitamins

HCT-15 and HCT116-colon carcinoma

-   -   RPMI 1640+10% FBS+1% L-glutamine+1% P/S

Drug Resistant Cell Lines

-   -   KB3.1—colon epidermal carcinoma; parental cell line    -   Iscove's+10% FBS+1% L-glutamine +1% P/S

KBV1—p-glycoprotein associated multi-drug resistant cell line

-   -   RPMI 1640+10% FBS+1% L-glutamine+1% P/S+0.2 ug/mL Vinblastine

KB85-p-glycoprotein associated multi-drug resistant cell line

-   -   DMEM+10% FBS+1% L-glutamine+1% P/S+10 ng/mL Colchicine

Preferred compounds of the invention have a biological activity asmeasured by an GI₅₀ of less than about 1 mM in assay protocols describedwith some embodiments having biological activity of less than about 25μM, with other embodiments having biological activity of less than about1000 nM, and with still other embodiment having a GI₅₀ of less thanabout 100 nM.

Example 15 Clonogenic Softagar Assay Protocol

Human cancer cells are plated at a density of 3×10⁵ cells per well in a6-well plate. The next day, a compound of interest at a certainconcentration is added to each well. After 24 and 48 hours ofincubation, the cells are harvested, washed and counted. The followingsteps are performed using the Multimek 96 robot. Then, 500 viable cellsper well are plated in a 96-well plate that is coated with PolyHema toprevent attachment of the cells to the bottom of the well. Agarose (3%stock) is melted, diluted in warmed media and added to the cells to afinal concentration of 0.5%. After the soft agar solidified, the platesare incubated at 37° C. for 6 days. Alamar blue dye is added to cellsand plates are incubated for an additional 6 hours. The optical densitychange is measured on a Tecan plate reader and is considered tocorrelate with the number of colonies formed in soft agar. A cancerouscell is able to grow on the agar and thus will show an increase inoptical density. A reading of decreased optical density means that thecancer cells are being inhibited. It is contemplated that compounds ofthis invention will exhibit a decrease in optical density.

1. A compound of formula II:

wherein: n is 1, 2, or 3; p is 0, 1, 2, 3, or 4; R³ and R⁴ areindependently selected from the group consisting of hydrogen, hydroxy,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic, provided that only 1 of R³ or R⁴ is hydroxy;or R³ and R⁴ together with the nitrogen atom pendent thereto join toform a heterocyclic or substituted heterocyclic; R¹⁰ is selected fromthe group consisting of hydrogen, alkyl optionally substituted with asubstituent selected from the group consisting of hydroxy, alkoxy,substituted alkoxy, amino, substituted amino, acylamino, halo,nitrogen-containing heterocycle, substituted nitrogen-containingheterocycle, nitrogen-containing heteroaryl, and substitutednitrogen-containing heteroaryl; R¹¹ is selected from the groupconsisting of cyano, alkyl, alkenyl, alkynyl, —CF₃, alkoxy, halo, andhydroxy, provided that when p is 2-4, then each R¹¹ may be the same ordifferent; R¹² is alkyl; R¹³ is hydrogen or alkyl, R¹⁴ is selected fromthe group consisting of hydrogen, halo, and alkyl; or R⁴ and R¹⁰,together with the atoms bound thereto, form a heterocyclic orsubstituted heterocyclic group; A² is selected from the group consistingof aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, cycloalkyl, and substitutedcycloalkyl; or a pharmaceutically acceptable salt or ester thereof. 2.The compound of claim 1, wherein R¹² is selected from the groupconsisting of isopropyl, t-butyl, and propyl.
 3. The compound of claim1, wherein R¹³ is hydrogen.
 4. The compound of claim 1, wherein R³and/or R⁴ is selected from the group consisting of alkyl, substitutedalkyl, or cycloalkyl, wherein the alkyl, substituted alkyl or cycloalkylis selected from the group consisting of methyl, methoxyethyl,furan-2-ylmethyl, 2-hydroxyethyl, cyclopropyl and isopropyl.
 5. Thecompound of claim 1, wherein R³ and/or R⁴ is aryl or substituted aryl,wherein the aryl or substituted aryl is selected from the groupconsisting of 4-cyanophenyl, 3,4-difluorophenyl, 2,3,5-trifluorophenyl,3,5-dinitrophenyl, and phenyl.
 6. The compound of claim 1, wherein R³and/or R⁴ is heteroaryl or substituted heteroaryl, wherein theheteroaryl or substituted heteroaryl is selected from the groupconsisting of thiophen-2-yl, 3,5-dimethylisoxazol-4-yl, and2,6-dichloropyridin-4-yl.
 7. The compound of claim 1, wherein R³ and/orR⁴ is a heterocyclic group or substituted heterocyclic group, whereinthe heterocyclic or substituted heterocyclic group istetrahydropyran-4-yl or 4-(ethoxycarbonyl)piperidin-4-yl.
 8. Thecompound of claim 1, wherein either of R³ or R⁴ or both of R³ and R⁴ arehydrogen.
 9. The compound of claim 1, wherein one of R³ or R⁴ ishydroxy.
 10. The compound of claim 1, wherein R³ and R⁴ are cyclizedwith the nitrogen atom bound thereto to form a heterocyclic, substitutedheterocyclic, heteroaryl or substituted heteroaryl, wherein theheterocyclic, substituted heterocyclic, heteroaryl or substitutedheteroaryl is selected from the group consisting of1,1-dioxothiamorpholin-N-yl, 1-oxothiamorpholin-1-yl,2-(aminomethylene)pyrrolidin-N-yl, 2-(methoxycarbonyl)pyrrolidin-N-yl,2,6-dimethylmorpholin-N-yl, 3-hydroxypiperidin-N-yl,3-hydroxypyrrolidin-N-yl, 4-(butylsulfonyl)piperazin-N-yl,4-(cyclopropylsulfonyl)piperazin-N-yl, 4-(dimethylamino)piperidin-N-yl,4-(ethoxycarbonyl)piperazin-N-yl, 4-(ethylsulfonyl)piperazin-N-yl,4-(isopropylsulfonyl)piperazin-N-yl, 4-(methylcarbonyl)piperazin-N-yl,4-(methylsulfonyl)piperidin-N-yl, 4-(methysulfonyl)piperazin-N-yl,4-(morpholin-N-yl)piperidin-N-yl, 4-(piperidin-N-yl)piperidin-N-yl,4-(propylsulfonyl)piperazin-N-yl, 4-cyclohexylpiperazin-N-yl,4-hydroxypiperidin-N-yl, 4-isopropylpiperazin-4-yl,4-methylpiperidin-N-yl, isoxazolidin-2-yl, morpholin-N-yl,piperazin-N-yl, piperidin-N-yl, 2-(hydrazinocarbonyl)pyrrolidin-N-yl andpyrrolidin-N-yl.
 11. The compound of claim 1, wherein R¹⁰ is selectedfrom the group consisting of —(CH₂)₃NH₂, —(CH₂)₂CH(CH₂OH)NH₂,—CH₂CH(F)CH₂NH₂, —CH₂-[2-(CH₂OH)pyrrolidin-3-yl],—CH₂-[4-(OH)pyrrolidin-3-yl], —CH₂—C(F)(spiropyrrolidin-3-yl),—(CH₂)₂CH(CH₂F)NH₂, —(CH₂)₂C(CH₃)₂NH₂, —(CH₂)₂CH(CH₃)NH₂,—(CH₂)₂CH(CH₂OCH₃)NH₂, —(CH₂)₂CH(CH₂F)NHC(O)-[(2-CH₃NHC(O))benzene], and—(CH₂)₂CH(CH₂F)-1,3-dioxo-1,3-dihydroisoindole.
 12. The compound ofclaim 1, wherein

is selected from the group consisting of phenyl, 3-chlorophenyl,3-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, and2,3,5-trifluorophenyl.
 13. The compound of claim 1, wherein R¹⁴ ishydrogen.
 14. The compound of claim 1, wherein A² is aryl or substitutedaryl.
 15. The compound of claim 1, wherein R² is t-butyl, R¹³ and R³ arehydrogen, n is 1, A² is phenyl, p is 1 or 2 and R¹ is halo.
 16. Thecompound of claim 1, wherein R¹² is t-butyl, R¹³ and R³ are hydrogen, nis 1, A² is phenyl, R¹⁰ is substituted alkyl, wherein substituted alkylis selected from the group consisting of —(CH₂)₃NH₂, —CH₂CH(F)CH₂NH₂,—(CH₂)₂CH(CH₂F)NH₂, —(CH₂)₂CH(CH₂OCH₃)NH₂, —(CH₂)₂CH(CH₃)NH₂,—(CH₂)₂C(CH₃)₂NH₂ and —(CH₂)₂CH(CH₂OH)NH₂.
 17. The compound of claim 1,wherein R¹² is t-butyl, R¹³ is hydrogen, R³ is hydrogen, n is 1, A² isphenyl, R¹¹ is fluoro, R⁴ is hydrogen, and R⁴ is alkyl.
 18. The compoundof claim 1, wherein R¹² is isopropyl and R¹¹ is chloro.
 19. A compoundselected from the group consisting of:N-(3-aminopropyl)-N-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}morpholine-4-carboxamide;N-(3-aminopropyl)-N-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}piperidine-1-carboxamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperidine-1-carboxamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′,N′-dimethylurea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-methoxyethyl)urea;methyl(2S)-1-({(3-aminopropyl)[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]amino}carbonyl)pyrrolidine-2-carboxylate;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-hydroxyurea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]pyrrolidine-1-carboxamide;(2R)-2-(aminomethyl)-N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]pyrrolidine-1-carboxamide;(3S)—N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide;(3R)—N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-methylurea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-1-carboxamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′-bipiperidine-1′-carboxamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-thien-2-ylurea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-thien-3-ylurea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(3,5-dimethylisoxazol-4-yl)urea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2,6-dichloropyridin-4-yl)urea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-furylmethyl)urea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(4-cyanophenyl)urea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(3,4-difluorophenyl)urea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(3,5-dinitrophenyl)urea;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-phenylurea;(3R)—N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-1-carboxamide;(3R)—N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1-carboxamide;(3S)—N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1-carboxamide;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′,N′-dimethylurea;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-phenylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′,N′-dimethylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-phenylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-methoxyethyl)urea;4-acetyl-N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-1-carboxamide;(4R)—N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-hydroxyisoxazolidine-2-carboxamide;(3R)—N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1-carboxamide;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-methoxyethyl)urea;(3R)—N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide;(3S)—N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypyrrolidine-1-carboxamide;(3S)—N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-3-hydroxypiperidine-1-carboxamide;ethyl4-({[(2S)-3-amino-2-fluoropropyl][(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]amino}carbonyl)piperazine-1-carboxylate;ethyl4-({[(2R)-3-amino-2-fluoropropyl][(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]amino}carbonyl)piperazine-1-carboxylate;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(ethylsulfonyl)piperazine-1-carboxamide;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-hydroxypiperidine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-hydroxypiperidine-1-carboxamide;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′-bipiperidine-1′-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′,-bipiperidine-1-carboxamide;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-methylpiperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-methylpiperazine-1-carboxamide;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-hydroxyethyl)-N′-methylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-hydroxyethyl)-N′-methylurea;1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]tetrahydropyrimidin-2(1H)-one;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(2-hydroxyethyl)-N′-methylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(3,4-difluorophenyl)urea;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-thien-3-ylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-thien-3-ylurea;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-morpholin-4-ylpiperidine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-morpholin-4-ylpiperidine-1-carboxamide;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]morpholine-4-carboxamide;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(methylsulfonyl)piperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(methylsulfonyl)piperazine-1-carboxamide;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-cyclohexylpiperazine-1-carboxamide;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(4-cyanophenyl)urea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(4-cyanophenyl)urea;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(propylsulfonyl)piperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(propylsulfonyl)piperazine-1-carboxamide;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(isopropylsulfonyl)piperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(isopropylsulfonyl)piperazine-1-carboxamide;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(cyclopropylsulfonyl)piperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(cyclopropylsulfonyl)piperazine-1-carboxamide;N-[(2S)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(butylsulfonyl)piperazine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(butylsulfonyl)piperazine-1-carboxamide;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4′-bipiperidine-1-carboxamide;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(4-cyanophenyl)urea;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-(3,4-difluorophenyl)urea;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S)-3-fluoropyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3R)-3-fluoropyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(2S,3S)-2-(hydroxymethyl)pyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-tetrahydro-2H-pyran-4-ylurea;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N′-tetrahydro-2H-pyran-4-ylurea;N-(3-amino-2-fluoropropyl)-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(dimethylamino)piperidine-1-carboxamide;N-[(2R)-3-amino-2-fluoropropyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(dimethylamino)piperidine-1-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S,4S)-4-hydroxypyrrolidin-3-yl]methyl}-1,4′-bipiperidine-1′-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-[(3-fluoropyrrolidin-3-yl)methyl]-4-(methylsulfonyl)piperazine-1-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3S)-3-fluoropyrrolidin-3-yl]methyl}-4-(methylsulfonyl)piperazine-1-carboxamide;N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-N-{[(3R)-3-fluoropyrrolidin-3-yl]methyl}-4-(methylsulfonyl)piperazine-1-carboxamide;N-[(3R)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(methylsulfonyl)piperazine-1-carboxamide;N-[(3S)-3-amino-4-hydroxybutyl]-N-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-(methylsulfonyl)piperazine-1-carboxamide;1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;1,1-Dioxo-1-thiomorpholine-4-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Methanesulfonyl-piperidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;1,1-Dioxo-1-thiomorpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Methanesulfonyl-piperidine-1-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea;1-(3-Amino-3-methyl-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;1-(3-Amino-3-methyl-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea;4-Methyl-piperazine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Methyl-piperazine-1-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-(3-Amino-3-methyl-butyl)-1-{(R)-1-[1-benzyl-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea;Morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;Pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Pyrrolidine-1-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Pyrrolidine-1-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-methoxy-butyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;Pyrrolidine-1-carboxylic acid((S)-3-amino-4-methoxy-butyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid ((S)-3-amino-4-methoxy-butyl)-{(R)—-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1,1-Dioxo-1-thiomorpholine-4-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-2-fluoro-propyl)-1-{(R)-1-[1-(3-fluoro-benzyl)-4-(3-fluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-urea;1-(3-Amino-propyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;1-(3-Amino-propyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;1-(3-Amino-propyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-(3,5-dimethyl-isoxazol-4-yl)-urea;Pyrrolidine-1-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Isoxazolidine-2-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Methanesulfonyl-piperazine-1-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Methanesulfonyl-piperidine-1-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((S)-3-amino-4-methoxy-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;Morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1,1-Dioxo-1-thiomorpholine-4-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3,3-dimethyl-urea;4-Methanesulfonyl-piperazine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-(3,5-di-methyl-isoxazol-4-yl)-urea;1,1-Dioxo-1-thiomorpholine-4-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Isoxazolidine-2-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Thiomorpholine-4-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Isoxazolidine-2-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Pyrrolidine-1-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1,1-Dioxo-1-thiomorpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-Oxo-1-thiomorpholine-4-carboxylic acid(3-amino-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((S)-3-amino-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Methanesulfonyl-piperazine-1-carboxylic acid((S)-3-amino-2-fluoro-propyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,3,5-trifluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,3,5-trifluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Morpholine-4-carboxylic acid((R)-3-amino-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;(2R,6S)-2,6-Dimethyl-morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-Isopropyl-piperazine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-isopropyl-urea;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-cyclopropylmethyl-urea;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-(tetrahydro-pyran-4-yl)-urea;Morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(S)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;4-(3-((S)-3-Amino-4-fluoro-butyl)-3-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-ureido)-piperidine-1-carboxylicacid ethyl ester; (2S,6R)-2,6-Dimethyl-morpholine-4-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;(S)-3-Hydroxy-pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;(R)-3-Hydroxy-pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;1-((S)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-cyclopropyl-urea;(S)-2-Hydrazinocarbonyl-pyrrolidine-1-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;(S)-1-((3-Amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-carbamoyl)-pyrrolidine-2-carboxylicacid methyl ester;1-((R)-3-Amino-4-fluoro-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;1-((S)-3-Amino-4-methoxy-butyl)-1-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-urea;Morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-hydroxy-benzyl)-4-(2,3,5-trifluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;(2S,6R)-2,6-Dimethyl-morpholine-4-carboxylic acid((S)-3-amino-4-fluoro-butyl)-{(R)-1-[1-(3-hydroxy-benzyl)-4-(2,3,5-trifluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;Pyrrolidine-1-carboxylic acid((R)-3-amino-4-fluoro-butyl)-{(R)-1-[1-benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-amide;N-[(3S)-3-amino-4-fluorobutyl]-N-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-N′-hydroxyurea;N-[(3R)-3-amino-4-fluorobutyl]-N-{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-N′-hydroxyurea;1-{(R)-1-[1-Benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-1-[(S)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-fluoro-butyl]-3-methyl-urea;andN—[(S)-3-(1-{(R)-1-[1-Benzyl-4-(2,5-difluoro-phenyl)-1H-imidazol-2-yl]-2,2-dimethyl-propyl}-3-methyl-ureido)-1-fluoromethyl-propyl]-N′-methyl-phthalamide,or a pharmaceutically acceptable salt or ester thereof.
 20. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable carrier. 21.The composition of claim 20 further comprising at least one agent forthe treatment of cancer.
 22. The composition of claim 21, wherein theagent for the treatment of cancer is selected from the group consistingof irinotecan, topotecan, gemcitabine, imatinib, trastuzumab,5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel,paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids,anthracyclines, rituximab, and trastuzumab.
 23. The compound of claim 1,wherein A² is phenyl, 3-fluorophenyl or 3-hydroxyphenyl.